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Background & Aims Patients with advanced hepatocellular carcinoma (aHCC) and Child-Pugh B liver function are often excluded from clinical trials. In previous studies, overall survival for these patients treated with sorafenib was ∼3–5 months; thus, new treatments are needed. Nivolumab, alone or in combination with ipilimumab, is conditionally approved in the United States to treat patients with aHCC who previously received sorafenib. We describe nivolumab monotherapy outcomes in patients with Child-Pugh B status. Methods This phase I/II, open-label, non-comparative, multicentre trial (27 centres) included patients with Child-Pugh B (B7–B8) aHCC. Patients received intravenous nivolumab 240 mg every 2 weeks until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1) and duration of response. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0. Results Twenty-five sorafenib-naive and 24 sorafenib-treated patients began treatment between November 2016 and October 2017 (median follow-up, 16.3 months). Investigator-assessed ORR was 12% (95% CI 5–25%) with 6 patients responding; disease control rate was 55% (95% CI 40–69%). Median time to response was 2.7 months (interquartile range, 1.4–4.2), and median duration of response was 9.9 months (95% CI 9.7–9.9). Treatment-related adverse events (TRAEs) were reported in 25 patients (51%) and led to discontinuation in 2 patients (4%). The most frequent grade 3/4 TRAEs were hypertransaminasemia (n = 2), amylase increase (n = 2), and aspartate aminotransferase increase (n = 2). The safety of nivolumab was comparable to that in patients with Child-Pugh A aHCC. Conclusions Nivolumab showed clinical activity and favourable safety with manageable toxicities, suggesting it could be suitable for patients with Child-Pugh B aHCC. Lay summary In patients with advanced hepatocellular carcinoma, almost all systemic therapies require very good liver function, i.e. Child-Pugh A status. The evidence from this study suggests that nivolumab shows clinical activity and an acceptable safety profile in patients with hepatocellular carcinoma with Child-Pugh B status who have mild to moderate impairment of liver function or liver decompensation that might rule out other therapies. Further studies are warranted to assess the safety and efficacy of nivolumab in this patient population. Clinical trial number NCT01658878 .

Background & Aims: Nivolumab, a programmed death (PD)-1 (PD-1) inhibitor, led to durable responses, manageable safety, and increased survival in patients with advanced hepatocellular carcinoma (HCC). In our retrospective analysis, we studied the immunobiology and potential associations between biomarkers and outcomes with nivolumab in HCC. Methods: Fresh and archival tumour samples from dose-escalation and dose-expansion phases of the CheckMate 040 trial were analysed by immunohistochemistry and RNA sequencing to assess several inflammatory gene expression signatures, including CD274 (PD-ligand 1 [PD-L1]), CD8A, LAG3, and STAT1. Biomarkers were assessed for association with clinical outcomes (best overall response by blinded independent central review per RECIST v1.1 and overall survival [OS]). Results: Complete or partial tumour responses were observed in PD-L1–positive and PD-L1–negative patients treated with nivolumab monotherapy. Median OS was 28.1 (95% CI 18.2–n.a.) vs. 16.6 months (95% CI 14.2–20.2) for patients with tumour PD-L1 ≥1% vs., Graphical Abstract

Background CheckMate 040 assessed the efficacy and safety of nivolumab in patients with advanced hepatocellular carcinoma (HCC). Understanding the safety profile of nivolumab is needed to support the management of treatment‐related adverse events (TRAEs). This analysis assessed the safety of nivolumab monotherapy in the phase I/II, open‐label CheckMate 040 study. Materials and Methods Select TRAEs (sTRAEs; TRAEs with potential immunologic etiology requiring more frequent monitoring) occurring between first dose and 30 days after last dose were analyzed in patients in the dose‐escalation and ‐expansion phases. Time to onset (TTO), time to resolution (TTR), and recurrence of sTRAEs were assessed, and the outcome of treatment with immune‐modulating medication (IMM) was evaluated. Results The analysis included 262 patients. The most common sTRAE was skin (35.5%), followed by gastrointestinal (14.5%) and hepatic (14.1%) events; the majority were grade 1/2, with 10.7% of patients experiencing grade 3/4 events. One patient had grade 5 pneumonitis. Median (range) TTO ranged from 3.6 (0.1–59.9) weeks for skin sTRAEs to 47.6 (47.1–48.0) weeks for renal sTRAEs. Overall, 68% of sTRAEs resolved, with median (range) TTR ranging from 3.7 (0.1–123.3+) weeks for gastrointestinal sTRAEs to 28.4 (0.1–79.1) weeks for endocrine sTRAEs. Most gastrointestinal and all hepatic events resolved with treatment in accordance with established toxicity management algorithms. In 57 patients (40%), sTRAEs were managed with IMM. Reoccurrence of sTRAEs was uncommon following rechallenge with nivolumab. Conclusion Nivolumab demonstrated a manageable safety profile in this analysis of patients with advanced HCC. A majority of sTRAEs resolved with treatment. Implications for Practice Nivolumab is a viable treatment option for patients with previously treated advanced hepatocellular carcinoma as it has demonstrated durable tumor responses and promising survival. Nivolumab has a manageable safety profile. The most common select treatment‐related adverse events (sTRAEs) in this analysis were skin related (35%). Gastrointestinal and hepatic sTRAEs were observed in approximately 14% of patients. The majority of sTRAEs resolved (68%). Safety events are easier to manage if addressed early. Patient education on signs and symptoms to watch out for and the importance of early reporting and consultation should be emphasized., The CheckMate 040 study assessed the efficacy and safety of nivolumab in patients with advance hepatocellular carcinoma. This article focuses on the safety of nivolumab monotherapy and associated treatment‐related adverse events.

Purpose Metastatic esophagogastric cancer treatments after failure of second-line chemotherapy are limited. Nivolumab demonstrated superior overall survival (OS) versus placebo in Asian patients with advanced gastric or gastroesophageal junction cancers. We assessed the safety and efficacy of nivolumab and nivolumab plus ipilimumab in Western patients with chemotherapy-refractory esophagogastric cancers. Patients and Methods Patients with locally advanced or metastatic chemotherapy–refractory gastric, esophageal, or gastroesophageal junction cancer from centers in the United States and Europe received nivolumab or nivolumab plus ipilimumab. The primary end point was objective response rate. The association of tumor programmed death-ligand 1 status with response and survival was also evaluated. Results Of 160 treated patients (59 with nivolumab 3 mg/kg, 49 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, 52 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg), 79% had received two or more prior therapies. At the data cutoff, investigator-assessed objective response rates were 12% (95% CI, 5% to 23%), 24% (95% CI, 13% to 39%), and 8% (95% CI, 2% to 19%) in the three groups, respectively. Responses were observed regardless of tumor programmed death-ligand 1 status. With a median follow-up of 28, 24, and 22 months across the three groups, 12-month progression-free survival rates were 8%, 17%, and 10%, respectively; 12-month OS rates were 39%, 35%, and 24%, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 47%, and 27% of patients in the three groups, respectively. Conclusion Nivolumab and nivolumab plus ipilimumab demonstrated clinically meaningful antitumor activity, durable responses, encouraging long-term OS, and a manageable safety profile in patients with chemotherapy-refractory esophagogastric cancer. Phase III studies evaluating nivolumab or nivolumab plus ipilimumab in earlier lines of therapy for esophagogastric cancers are underway.

Purpose Patients with squamous non–small-cell lung cancer (NSCLC) have poor prognosis and limited treatment options. This randomized, double-blind, phase III study investigated the efficacy and safety of first-line ipilimumab or placebo plus paclitaxel and carboplatin in advanced squamous NSCLC. Patients and Methods Patients with stage IV or recurrent chemotherapy-naïve squamous NSCLC were randomly assigned (1:1) to receive paclitaxel and carboplatin plus blinded ipilimumab 10 mg/kg or placebo every 3 weeks on a phased induction schedule comprising six chemotherapy cycles, with ipilimumab or placebo from cycles 3 to 6 and then, after induction treatment, ipilimumab or placebo maintenance every 12 weeks for patients with stable disease or better. The primary end point was overall survival (OS) in patients receiving at least one dose of blinded study therapy. Results Of 956 randomly assigned patients, 749 received at least one dose of blinded study therapy (chemotherapy plus ipilimumab, n = 388; chemotherapy plus placebo, n = 361). Median OS was 13.4 months for chemotherapy plus ipilimumab and 12.4 months for chemotherapy plus placebo (hazard ratio, 0.91; 95% CI, 0.77 to 1.07; P = .25). Median progression-free survival was 5.6 months for both groups (hazard ratio, 0.87; 95% CI, 0.75 to 1.01). Rates of grade 3 or 4 treatment-related adverse events (TRAEs), any-grade serious TRAEs, and TRAEs leading to discontinuation were numerically higher with chemotherapy plus ipilimumab (51%, 33%, and 28%, respectively) than with chemotherapy plus placebo (35%, 10%, and 7%, respectively). Seven treatment-related deaths occurred with chemotherapy plus ipilimumab, and one occurred with chemotherapy plus placebo. Conclusion The addition of ipilimumab to first-line chemotherapy did not prolong OS compared with chemotherapy alone in patients with advanced squamous NSCLC. The safety profile of chemotherapy plus ipilimumab was consistent with that observed in previous lung and melanoma studies. Ongoing studies are evaluating ipilimumab in combination with nivolumab in this population.

483 Background: SOR is approved as 1L therapy for pts with aHCC, but there is still an unmet need to help improve or maintain HRQoL. This phase 3 study compared HRQoL of NIVO vs SOR as 1L therapy in pts with aHCC as an exploratory endpoint. Methods: FACT-Hep was administered cycle 1, day 1 and every other cycle. The effect of NIVO vs SOR on HRQoL using FACT-Hep was assessed via repeated measures mixed models (MMRM). Kaplan–Meier curves and Cox proportional-hazards models determined between-treatment differences in time to first and time until definitive deterioration (TTD/TUDD) based on prespecified thresholds for minimally important differences. The GP5 item from FACT-Hep was used to assess the burden associated with treatment side effects. Results: 743 pts with aHCC were randomized to NIVO (n = 371) or SOR (n = 372). Median OS was 16.4 mo for NIVO, 14.7 mo for SOR (HR 0.85 [95% CI 0.72–1.02]; P = 0.0752). ORR was 15% for NIVO, 7% for SOR (OR 2.41 [95% CI 1.48–3.92]). HRQoL scores were completed at baseline by 94.6% and 92.5% of participants, respectively, and were similar (FACT-Hep total: NIVO 140.7 [SD 21.5] and SOR 140. 6 [SD 19.1]. Questionnaire compliance rates exceeded 70% at most visits. MMRM analyses yielded clinically meaningful and statistically significant least squares means differences favoring NIVO on FACT-Hep total (10.1 [95% CI 7.3–13.0]), physical well-being (PWB; 2.0 [95% CI 1.4–2.6]), and functional well-being (FWB; 2.5 [95% CI 1.7–3.2]) scores. No sub-scales favored sorafenib. TTD was significantly delayed in NIVO for FACT-Hep total (HR 0.62 [95% CI 0.51–0.74]), PWB (HR 0.62 [95% CI 0.52–0.74]), FWB (HR 0.73 [95% CI 0.61–0.88]), and hepatobiliary cancer subscale (HR 0.57 [95% CI 0.48–0.69]). TUDD results were consistent with TTD. A greater proportion of NIVO pts did not experience increased burden of side effects (50%–67.7%) compared with SOR (26.8%–45%) based on the GP5 item. Conclusions: These patient-reported findings demonstrate that pts taking NIVO had superior HRQoL and reduced side effect burden, further supporting clinical data showing a treatment benefit for 1L NIVO in aHCC. Clinical trial information: NCT02576509.

512 Background: NIVO monotherapy is approved in the United States and other countries for pts with HCC treated with sorafenib (SOR) based on CheckMate 040 (NCT01658878) results, which reported 14% objective response rate (ORR) and 16-month median overall survival (mOS; El-Khoueiry et al. Lancet 2017). Primary efficacy and safety of NIVO + IPI in pts with aHCC previously treated with SOR were presented recently (Yau et al. J Clin Oncol 2019). Here, we will present subgroup analyses from this study. Methods: Pts were randomized to 3 arms: [A] NIVO 1 mg/kg + IPI 3 mg/kg Q3W (4 doses) or [B] NIVO 3 mg/kg + IPI 1 mg/kg Q3W (4 doses), each followed by NIVO 240 mg Q2W, or [C] NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W. Treatment continued until intolerable toxicity or disease progression. Primary endpoints included safety/tolerability, ORR, and duration of response (DOR; investigator assessment per RECIST v1.1). Key secondary endpoints included disease control rate (DCR), OS, and progression-free survival (blinded independent central review [BICR] per RECIST v1.1); key exploratory endpoints included ORR (BICR per RECIST v1.1). Data cutoff was January 2019. Results: A total of 148 pts were randomized. Minimum OS follow-up from last pt randomization date to data cutoff was 28 months. At baseline, 34% of all pts had vascular invasion; 82% had extrahepatic spread; and 91% had Barcelona Clinic Liver Cancer stage C; 84% discontinued SOR because of disease progression and 14% because of toxicity. For all treated pts, ORR was 31% (7 had complete response), with median DOR of 17 months; DCR was 49%; the 30-month OS rate was 37%. NIVO + IPI was well tolerated; 38% of pts had grade 3–4 treatment-related adverse events (TRAEs; most common any grade: pruritus and rash; most common grade 3–4: aspartate aminotransferase increase and lipase increase); 5% had grade 3–4 TRAEs leading to discontinuation. Subgroup analyses based on duration of prior SOR therapy and other pt characteristics will be presented. Conclusions: NIVO + IPI led to clinically meaningful benefits, with a manageable safety profile in pts previously treated with SOR. NIVO + IPI may provide a new treatment option for these pts. Clinical trial information: NCT01658878.

478 Background: The programmed death-1 inhibitor NIVO had durable responses and a manageable safety profile in pts with aHCC in CheckMate 040 (NCT01658878; El-Khoueiry et al. Lancet 2017) and is approved in the United States, Canada, Australia, and elsewhere for sorafenib (SOR)-treated pts with aHCC. In another CheckMate 040 cohort, NIVO + IPI combination therapy had durable responses in SOR-treated pts with aHCC, with objective response rates (ORRs) > 30% in each dosing arm (Yau et al. J Clin Oncol 2019). CABO is also approved for SOR-treated pts with aHCC; a pivotal phase 3 trial reported median overall survival (OS) of 10.2 mo (Abou-Alfa et al. N Engl J Med 2018). This is the first report of efficacy and safety of NIVO + CABO +/- IPI (doublet and triplet) combinations in pts with aHCC. Methods: SOR-naive or -experienced pts with aHCC were randomized to 2 arms: [1] NIVO 240 mg Q2W + CABO 40 mg daily or [2] NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W + CABO 40 mg daily. Treatment continued until intolerable toxicity or disease progression. Primary endpoints included ORR (investigator assessed using RECIST v1.1) and safety/tolerability. Data cutoff was January 2019. Results: 71 pts were randomized to NIVO + CABO (n = 36) or NIVO + IPI + CABO (n = 35). Investigator-assessed ORR was 17% (6 pts with partial response [PR]) in the NIVO + CABO arm and 26% (9 pts with PR) in the NIVO + IPI + CABO arm. Disease control rate was 81% for the NIVO + CABO arm and 83% for the NIVO + IPI + CABO arm; median progression-free survival was 5.5 mo for the NIVO + CABO arm and 6.8 mo for the NIVO + IPI + CABO arm. Median OS was not reached in either arm. Grade 3-4 treatment-related adverse events (TRAEs) were reported in 15 pts (42%) in the NIVO + CABO arm and 25 pts (71%) in the NIVO + IPI + CABO arm and led to discontinuation in 1 (3%) and 7 (20%) pts, respectively. No new safety signals were observed in either arm. Updated data describing the efficacy and safety of the combinations will be shown. Conclusions: In pts with aHCC, NIVO + CABO +/- IPI combination therapy led to clinically meaningful responses. Although the triplet had a higher rate of TRAEs observed than the doublet regimen, the majority of AEs were manageable and reversible. Clinical trial information: NCT01658878.

Purpose There is evidence from nonrandomized studies that a proportion of ipilimumab-treated patients with advanced melanoma experience long-term survival. To demonstrate a long-term survival benefit with ipilimumab, we evaluated the 5-year survival rates of patients treated in a randomized, controlled phase III trial. Patients and Methods A milestone survival analysis was conducted to capture the 5-year survival rate of treatment-naive patients with advanced melanoma who received ipilimumab in a phase III trial. Patients were randomly assigned 1:1 to receive ipilimumab at 10 mg/kg plus dacarbazine (n = 250) or placebo plus dacarbazine (n = 252) at weeks 1, 4, 7, and 10 followed by dacarbazine alone every 3 weeks through week 22. Eligible patients could receive maintenance ipilimumab or placebo every 12 weeks beginning at week 24. A safety analysis was conducted on patients who survived at least 5 years and continued to receive ipilimumab as maintenance therapy. Results The 5-year survival rate was 18.2% (95% CI, 13.6% to 23.4%) for patients treated with ipilimumab plus dacarbazine versus 8.8% (95% CI, 5.7% to 12.8%) for patients treated with placebo plus dacarbazine (P = .002). A plateau in the survival curve began at approximately 3 years. In patients who survived at least 5 years and continued to receive ipilimumab, grade 3 or 4 immune-related adverse events were observed exclusively in the skin. Conclusion The additional survival benefit of ipilimumab plus dacarbazine is maintained with twice as many patients alive at 5 years compared with those who initially received placebo plus dacarbazine. These results demonstrate a durable survival benefit with ipilimumab in advanced melanoma.

O1 Combinatorial CD8+ and PD-L1+ cell densities correlate with response and improved survival in non-small cell lung cancer (NSCLC) patients treated with durvalumab #### Sonja Althammer1, Keith Steele2, Marlon Rebelatto2, Tze Heng Tan1, Tobias Wiestler1, Guenter Schmidt1, Brandon Higgs2, Xia

Summary Background Few effective treatments exist for patients with advanced urothelial carcinoma that has progressed after platinum-based chemotherapy. We assessed the activity and safety of nivolumab in patients with locally advanced or metastatic urothelial carcinoma whose disease progressed after previous platinum-based chemotherapy. Methods In this phase 1/2, multicentre, open-label study, we enrolled patients (age ≥18 years) with urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra at 16 sites in Finland, Germany, Spain, the UK, and the USA. Patients were not selected by PD-L1 expression, but tumour PD-L1 membrane expression was assessed retrospectively. Patients received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression or treatment discontinuation because of unacceptable toxicity or other protocol-defined reasons, whichever occurred later. The primary endpoint was objective response by investigator assessment. All patients who received at least one dose of the study drug were included in the analyses. We report an interim analysis of this ongoing trial. CheckMate 032 is registered with ClinicalTrials.gov, NCT01928394. Findings Between June 5, 2014, and April 24, 2015, 86 patients with metastatic urothelial carcinoma were enrolled in the nivolumab monotherapy group and 78 received at least one dose of treatment. At data cutoff (March 24, 2016), the minimum follow-up was 9 months (median 15·2 months, IQR 12·9–16·8). A confirmed investigator-assessed objective response was achieved in 19 (24·4%, 95% CI 15·3–35·4) of 78 patients. Grade 3–4 treatment-related adverse events occurred in 17 (22%) of 78 patients; the most common were elevated lipase (four [5%]), elevated amylase (three [4%]), and fatigue, maculopapular rash, dyspnoea, decreased lymphocyte count, and decreased neutrophil count (two [3%] each). Serious adverse events were reported in 36 (46%) of 78 patients and eight (10%) had a serious adverse event judged to be treatment related. Two (3%) of 78 patients discontinued because of treatment-related adverse events (grade 4 pneumonitis and grade 4 thrombocytopenia) and subsequently died. Interpretation Nivolumab monotherapy was associated with a substantial and durable clinical response and a manageable safety profile in previously treated patients with locally advanced or metastatic urothelial carcinoma. These data support further investigation of nivolumab monotherapy in advanced urothelial carcinoma. Funding Bristol-Myers Squibb.

4014 Background: In the phase 3 ONO-12 study, 3rd- or later-line nivolumab (N) monotherapy prolonged OS vs placebo in Asian pts with adv G/GEJ cancer (median OS, 5.3 vs 4.1 mo; HR, 0.63; P < 0.0001; ASCO-GI 2017, Kang YK et al. J Clin Oncol. 2017;35 (suppl 4S) [abstract 2]). The phase 1/2 CheckMate 032 study showed favorable clinical activity of N ± ipilimumab (I) in Western pts with adv CTx-R G/E/GEJ cancer (NCT01928394). We report updated long-term follow-up data of G/E/GEJ pts in CheckMate 032. Methods: Pts received N 3 mg/kg Q2W (N3), N 1 mg/kg + I 3 mg/kg Q3W (N1+I3), or N 3 mg/kg + I 1 mg/kg Q3W (N3+I1). Primary endpoint was ORR. Secondary endpoints included DOR, OS, PFS, and safety. Efficacy in pts by PD-L1 status was assessed. Results: 160 heavily pretreated pts (79% had ≥ 2 prior Tx) were enrolled (N3, n = 59; N1+I3, n = 49; N3+I1, n = 52); 24% had PD-L1+ (≥ 1%) tumors. ORR was 12% in N3, 24% in N1+I3, and 8% in N3+I1. In pts with PD-L1 ≥ 1%, ORR was 19% (3/16) in N3, 40% (4/10) in N1+I3, and 23% (3/13) in N3+I1; in pts with PD-L1 < 1%, ORR was 12% (3/26), 22% (7/32), and 0% (0/30), respectively. Median DOR was 7.1 mo in N3, 7.9 mo in N1+I3, and NA in N3+I1. OS in all pts and in pts with PD-L1 ≥ 1% is in the Table. Grade 3–4 treatment-related AEs reported in ≥ 10% of pts in any treatment arm were diarrhea (N3, 2%; N1+I3, 14%; N3+I1, 2%), ALT increased (N3, 3%; N1+I3, 14%; N3+I1, 4%), and AST increased (N3, 5%; N1+I3, 10%; N3+I1, 2%). Conclusions: N ± I led to durable responses and long-term OS in heavily pretreated Western pts with adv G/E/GEJ cancer, which is consistent with the clinical activity observed in Asian pts in the ONO-12 study. Safety was consistent with prior reports. These data support ongoing investigation of N ± I in pts with adv G/E/GEJ cancer. Clinical trial information: NCT01928394. [Table: see text]

100Background: Patients (pts) with advanced (adv) SCLC after first-line platinum-based chemotherapy have limited options. Nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor, is approved for previously treated metastatic NSCLC in the US and for squamous NSCLC in the EU. Nivolumab + ipilimumab, a cytotoxic T-lymphocyte antigen-4 immune checkpoint inhibitor, has shown durable responses in multiple tumor types. CheckMate 032 was designed to evaluate nivolumab +/- ipilimumab in adv tumors including SCLC. Methods: AdvSCLC pts with progressive disease (PD) after ≥1 platinum-based chemotherapy, regardless of platinum sensitivity or tumor PD-1 ligand 1 (PD-L1) expression, were eligible. Pts received nivolumab ([mg/kg] N3 Q2W) or nivolumab + ipilimumab combination (N1 + I3 or N3 + I1 Q3W for 4 cycles then N3 Q2W). Primary endpoint was objective response rate (ORR). Additional endpoints were safety, overall survival (OS), progression-free survival (PFS), and biomarkers. Results: 180 pts were enrolled...

4501Background: Minimal antitumor activity of existing therapies and the observation of immune dysfunction in bladder cancer have prompted evaluation of immunotherapy in this malignancy. Nivolumab (fully human IgG4 programmed death-1 immune checkpoint inhibitor antibody) monotherapy has shown survival benefit in patients (pts) with melanoma, lung cancer, and renal cell carcinoma. Here, we report efficacy and safety of nivolumab monotherapy in pts with mUC after ≥1 prior line of platinum-based therapy in an open-label, multicenter phase I/II study (NCT01928394). Methods: Pts (unselected by PD-L1 expression status) with mUC received nivolumab 3 mg/kg intravenously every 2 weeks until progression or discontinuation. Primary endpoint was objective response rate (ORR; RECIST 1.1). Other endpoints included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: Of 78 treated pts (median age 65.5 years; range, 31–85), 65.4% had received ≥2 prior therapies. At a me...

468 Background: The cell-based therapeutic cancer vaccine MGN1601 consists of two active pharmaceutical ingredients in fixed combination. Fourfold gene-modified, allogeneic tumor cells expressing IL-7, GM-CSF, CD80, and CD154 through MIDGE gene expression vectors are combined with the DNA-based immunomodulator dSLIMas a TLR-9 agonist. In the phase I-II clinical trial (ASET trial) heavily pre-treated patients with metastatic renal cell carcinoma (mRCC) were enrolled. Methods: TheASET study has been conducted as a multicenter, open, single-arm phase I-II study. The treatment phase (TP) consisted of 8 intradermal vaccinations, administered within 12 weeks. We analysed known mRCC prognostic factors for their predictive value, i.e. safety laboratory and immunological parameters, quality of life, local reactions and other patients’ characteristics. Results: 19 patients from the ASET study, who received at least one vaccination (ITT population), were included in the biomarker evaluation. The median overall survival (mOS) in the ITT population is currently 25 weeks. mOS of patients who discontinued TP prematurely was only 10 weeks. However, mOS of those patients who completed at least TP is not yet mature for statistical calculation (NR), but is currently estimated as 69 weeks, resulting in a highly significant difference (10 weeks vs. NR, p < 0.001). Patients with an absolute lymphocyte counts (ALC) at baseline of ≥1,000/μL had increased overall survival (mOS NR vs. 16 weeks, p = 0.013), if compared to those with an ALC 3, bone and liver metastasis, high MSKCC score were identified as risk factors associated with lower overall survival. ALC ≥1,000/μL after three MGN1601 vaccinations (week 5) was even more significantly associated with increased overall survival (mOS NR vs. 17 weeks, p = 0.007). The NLR and quality of life improvement at week 5 as well as local reactions at injection sites seem to correlate with OS. Conclusions: MGN1601 shows promising efficacy in late stage mRCC patients. The identified parameters should be further investigated as potential biomarkers for efficacy. Clinical trial information: NCT01265368.

Introduction Standard chemotherapy is increasingly discontinued after successful “induction” in patients (pts) undergoing 1st line treatment for mCRC. MGN1703 is a synthetic DNA-based immunomodulator acting as an agonist of TLR-9 that has shown preclinical activity in mCRC. This study has been conducted to assess clinical efficacy, immunogenicity, and safety of MGN1703 as maintenance vs. placebo. Methods The IMPACT study is an international, multicenter, randomized double-blind placebo-controlled phase II/III study. Pts with mCRC showing disease control (CR, PR or SD) after 4.5 to 6 months of 1st-line standard therapy with FOLFOX/XELOX or FOLFIRI +/- bevacizumab (investigatoŕs choice) were included. Results Interim analysis of the unblinded data revealed a strong therapeutic effect compared to anticipated PFS. Therefore, patients were withheld from further randomization, according to a decision of the steering committee. In the ITT population (N = 55 pts), hazard ratio (HR) was 0.53 in favor of MGN1703 (p = 0.062). In the per-protocol population (excluding screening failures; N = 50), HR was 0.43 (p = 0.015). In the pre-defined target population (2 out of 3 factors: CEA Conclusions Maintenance therapy with MGN1703 after standard chemotherapy with or without bevacizumab, is associated with significantly improved progression-free survival compared to placebo and is accompanied by low toxicity. A confirmatory clinical study in patients with metastatic CRC is currently being planned. Disclosure M. Tschaika: Employment, stock ownership. M. Schmidt: Employment. B. Wittig: Stock ownership. All other authors have declared no conflicts of interest.

e14152 Background: Based on promising data from a phase 1 study of MGN1703 in patients with metastatic solid tumors including those with CRC, a phase 2-3 study was initiated in patients with advanced CRC having disease control after first-line therapy. MGN1703 is a synthetic DNA-based immunomodulator which acts as an agonist of toll-like receptor 9. The objective of the study is to assess efficacy and safety of treatment with MGN1703 in comparison to placebo. Methods: The IMPACT study is designed as an international, multicentric, randomized double-blind placebo-controlled phase 2-3 study. It is conducted in patients with advanced CRC showing disease control after 1st-line therapy with standard chemotherapy regimen. The study treatment is administered s.c. twice weekly (60 mg MGN1703 or placebo; ratio 2:1). The efficacy and safety of the study treatment will be evaluated based on extensive immunological tests, radiological assessment, safety laboratory results and assessments of the quality of life. The study treatment is continued until tumor progression, intolerable toxicity, exclusion criteria or withdrawal of consent. Results: Up to now, the patients received a maximum of 132 (mean: 32.1) treatment administrations, which equals 66 weeks. Drug-related adverse events (as assessed by the investigator) include mild fever, injection site itching, muscle aching, arthralgia, fatigue, paresthesia, rash, and moderate subfebril temperature and increased ANA in single patients. These represent only 16% of all adverse events reported in the study so far. Nine serious adverse events have been reported and only one was assessed as probably drug-related (“atypical pneumonia”). Local reactions reported in single patients include such symptoms as mild redness and swelling at injection site. Currently no laboratory or clinical signs of dose-limiting toxicities have been reported. Conclusions: The preliminary results of the ongoing clinical study in patients with advanced CRC show a good safety profile of the treatment with MGN1703 at the dosage of 60 mg. Most adverse events which were assessed as possibly drug-related belong to expected study drug reactions known for immune modulating drugs.

4636 Background: MGN1601 was tested in the first-in-man phase I-II clinical study in patients with advanced renal cell carcinoma (RCC) who failed several previous therapy lines and had no further standard therapy available. MGN1601 consists of two active pharmaceutical ingredients in fixed combination: fourfold gene-modified allogeneic tumor cells expressing IL-7, GM-CSF, CD80 and CD154 through MIDGE vectors and a TLR-9 agonist, the immunomodulator dSLIM. Methods: The ASET study is a multicentric, single-arm phase I-II clinical trial. Clinical response was evaluated using CT scans (RECIST 1.1 or immune related Response Criteria, irRC). Efficacy data were evaluated in terms of PFS and OS for the intended to treat and the treated per protocol (TPP) populations, clinical parameters and quality of life. Immune response was determined using DTH to MGN1601, LTT assay, frequency and activation of blood cells, and mRNA, chemokine and cytotoxic T cells analysis as well as tumor tissue evaluation. Results: Nine of 19 included patients completed the TPP, the others discontinued the study earlier due to PD. Median PFS in the TPP group was 12 wks (3 months) and OS (not reached yet) 46 wks (11 months). Three patients achieved disease control (1 PR, 2 SD) after 12 wks. Two patients are continuing treatment in the extension phase and are progression free since 37 and 46 wks, respectively. Re-evaluation of tumor response data using irRC revealed 1 additional patient with a delayed tumor response 4 wks after treatment stop. Herewith, 4 out of 9 TPP patients (45%) achieved disease control. Of 7 patients receiving targeted therapy upon stop of study treatment, 4 had substantial objective responses, providing evidence that the study drug is able to render their tumors more vulnerable to subsequent therapies. Immune analysis showed trends towards increases of T-, NKT-cell and pDC frequencies and other immune parameters in those patients with clinical responses, indicating anti-tumor immunity of study treatment. Conclusions: The therapeutic cancer vaccine MGN1601 shows promising efficacy in late stage mRCC patients. Results warrant further clinical studies with MGN1601.

Background. The first-in-man phase 1-2 clinical study (ASET study) of the cell-based therapeutic cancer vaccine MGN1601 included patients with advanced renal cell carcinoma (RCC) who failed previous therapies and had no further standard therapy available. MGN1601 consists of two active pharmaceutical ingredients in fixed combination: fourfold gene-modified allogeneic tumor cells expressing IL-7, GM-CSF, CD80 and CD154 through MIDGE® vectors and a TLR-9 agonist, the DNA-based immunomodulator dSLIM®. Methods. The ASET study is conducted as a multicentric, open, single-arm Phase 1-2 clinical trial. Clinical response (PD, SD, PR, CR) was evaluated using CT scans according to RECIST 1.1 criteria and immune related Response Criteria (irRC). The efficacy data were evaluated in terms of progression-free survival (PFS) and overall survival (OS) for the intended to treat (ITT) and the treated per protocol (TPP) populations of patients.Immune response was determined by the following parameters: ELISA of serum cytokines and chemokines, DTH to MGN1601, LTT assay to standard antigens, frequency and activation of plasmacytoid dendritic cells (pDC), myeloid dendritic cells (mDC), monocytes, natural killer cells (NK), NKT-, B-, and T cells. Blood mRNA and frequency of cytotoxic T cells by ELISPOT as well as tumor tissue were analyzed in a patient subgroup. Results. Nineteen patients, who had advanced stage RCC and failed up to 7 previous therapy lines (median 3 lines), were included. Nine of these patients completed the treatment phase per protocol (TPP), the others discontinued the study earlier due to PD. Currently, one patient is still in treatment phase. Median PFS in the TPP group was 12 weeks (3 months) and OS (not reached yet) 45 weeks (11 months). Three patients achieved disease control (one PR and two SD) after 12 weeks according to RECIST 1.1 criteria. Two patients are continuing treatment in the extension phase and are progression free since 37 and 46 weeks, respectively. Re-evaluation of tumor response data using irRC revealed one additional patient, who had a delayed tumor response 4 weeks after stop of treatment. Herewith, 4 out of 9 TPP patients (45%) achieved disease control. Of six patients receiving a targeted therapy following progress, four had substantial objective responses, suggesting that the study drug rendered their tumors more vulnerable to subsequent therapies. Immune analysis of the cell populations after 12 weeks showed trends towards increases of T cell, NKT-cell and pDC frequencies in those patients with clinical responses to the therapy, indicating anti-tumor immunity due to the study treatment. Conclusions. The therapeutic cancer vaccine MGN1601 shows promising efficacy in late stage mRCC patients. Results warrant further clinical studies with MGN1601. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-233. doi:1538-7445.AM2012-LB-233

398 Background: The purpose of this first-in-man phase 1-2 study is to assess safety and efficacy of treatment with investigational drug MGN1601 in patients with advanced renal cell carcinoma. MGN1601 consists of two active ingredients: genetically modified allogeneic (human) cells transfected with four different MIDGE vectors encoding IL-7, GM-CSF, CD80 and CD154 and a synthetic DNA-based immunomodulator dSLIM-30L1, a TLR-9 agonist, acting as adjuvant. Methods: The ASET study is conducted as multicenter, open, single-arm phase 1-2 study. The study therapy consists of 8 MGN1601 treatments administered as follows: the first 3 treatments are administered weekly, and the consecutive 5 treatments bi-weekly. Patients who achieve disease control are proposed to continue the therapy in an extension phase. Such patients receive 5 further applications up to week 120. In this study, safety and efficacy of the study treatment will be evaluated based on extensive clinical and laboratory assessments, monitoring of patients’ quality of life, immunological tests, and radiological investigations. Results: Eighteen patients have been included into the study so far and received up to 9 treatments with MGN1601. Eight patients completed the 12 week treatment per protocol (TPP). Two of these patients (25% of TPP) achieved disease control (one PR and one SD) after 12 weeks and currently continue the treatment in the extension phase. 48 adverse events were reported during the treatment phase. Of them, 10% were judged as possibly related, 23% unlikely and 67% as not drug-related by the investigators. Possible adverse events include mild fever, edema of the ankle, exanthema crook of the arm, pruritus crook of the arm and arthralgia intermittent. The therapy is well tolerated – no treatment-limiting toxicities or grade 2–4 toxicities occurred in these patients. Conclusions: The results of the clinical study in late stage RCC patients show promising efficacy and a favourable safety profile of the cell-based tumor vaccine consisting of genetically modified allogeneic transfected RCC cells and the immunomodulator.

633 Background: The synthetic DNA-based immunomodulator MGN1703 acts as an agonist of toll-like receptor 9. Based on promising data from a phase I study in patients with metastatic solid tumors including those with CRC, a phase II-III study was initiated in patients with advanced CRC having disease control after first-line therapy. The objective of the study is to assess efficacy and safety of the MGN1703 treatment in comparison to placebo. Methods: The IMPACT study is designed as a randomized double-blind placebo-controlled phase II-III study, which is conducted in patients with advanced CRC showing disease control after first-line therapy with standard chemotherapy regimen. The treatment is administered subcutaneously twice weekly in a ratio 2:1 (60 mg MGN1703 or placebo). The study is conducted in Germany, Austria, France, UK, Czech Republic and Russia, and 129 patients will be recruited into the study. The efficacy and safety of the study treatment will be evaluated based on extensive immunological tests, radiological assessment, safety laboratory results and assessments of the quality of life. The study treatment will be continued until tumor progression, intolerable toxicity, exclusion criteria or withdrawal of consent. Results: The majority of adverse events were assessed as not drug-related by the investigator. The remaining AEs include mild night sweat (not assessable), mild fever (at three occasions, possible related), and mild arthralgia (certain related) in one patient each. Three SAE have been reported so far of which one was assessed as probably drug-related – atypical pneumonia. Only in single patients local reactions such as mild redness and swelling at injection site were reported. No laboratory or clinical signs of autoimmunity or dose-limiting toxicities were reported, so far. Conclusions: With these preliminary safety results of the ongoing clinical study in patients with advanced CRC it could be shown that ttreatment with MGN1703 at the dosage of 60 mg is well tolerated and safe. Reported adverse events assessed as possibly drug-related belong to expected study drug reactions known for immune modulating drugs. These events were not accompanied by any signs of autoimmunity.

e15157 Background: The clinical study with MGN1601 was initiated after proven prophylactic and therapeutic anti-tumor activity and good safety profile of the study drug shown in several in-vivo mod...

392 Background: MGN1601 is a cell-based RCC tumor vaccine MGN1601 consisting of two active pharmaceutical ingredients: genetically modified allogeneic (human) cells transfected with four different MIDGE vectors encoding IL-7, GM-CSF, CD80 and CD154 and a synthetic DNA-based immunomodulator dSLIM-30L1, a TLR-9 agonist. The vaccine is being developed for treatment of patients with advanced RCC. Its prophylactic and therapeutic anti-tumor activity has been shown in several in-vivo models. A good safety profile of MGN1601 was shown in a wide program of acute and chronic toxicity studies. Based on these promising data, this phase 1/2 study was started in patients with advanced RCC. Methods: This multicentric open clinical study for the assessment of safety and efficacy of MGN1601 in patients with advanced RCC was initiated in October 2010. A total of 24 patients have to be recruited into the study. The treatment consists of 8 MGN1601 treatments administered as follows: the first 3 treatments are administered on a weekly basis, and the consecutive 5 treatments on a bi-weekly basis. The treatment dose contains 107 transfected tumor cells and 5 mg dSLIM per administration, which has been proven to be safe with a high safety margin in repeated toxicity studies. The efficacy and safety of the study treatment will be evaluated based on extensive immunological tests, radiological assessment, safety laboratory results and assessments of the quality of life. Here, the first safety data are presented. [Table: see text]

e15067 Background: MGN1601 is a cell-based tumor vaccine for the treatment of mRCC. MGN1601 consists of two active pharmaceutical ingredients. One consists of allogeneic, human tumor cells, derived...

e15104 Background: The cell-based tumor vaccine MGN1601 for the treatment of renal cell carcinoma (RCC), consists of two active pharmaceutical ingredients: First, genetically modified allogeneic (h...

Abstract 4730 Background The DNA-based immunomodulator MGN1703 stimulates the innate and cellular immune system mainly via the TLR9-receptor. The results of the recent in vivo experiments showed potent anti-tumor efficacy of MGN1703 in several mouse tumor models in prophylactic and therapeutic settings as well as a good safety profile in various animals. Two investigator-initiated pilot trials of MGN1703 as adjuvant in patients with metastatic solid tumors also showed good safety and tolerability of the drug as well as a positive effect on the response rate in patients treated with MGN1703. Patients/Methods In this Phase 1 clinical trial MGN1703 is administered subcutaneously in escalating doses (0.25 mg, 2 mg, 10 mg, 30 mg, and 60 mg; 3-6 patients per group) either in a single or in a multiple (2x / week over 6 weeks) dose regimen. Patients with metastatic tumors of the following entities are recruited for the study, if no other standard treatment options are available: Colorectal cancer, breast cancer, lung cancer, renal cell carcinoma and melanoma. Primary endpoints are evaluation of the safety and tolerability of escalating single doses and of escalating multiple doses of s.c. administered MGN1703, determination of the maximum tolerated dose (MTD) and dose limiting toxicity (DLT), and recommendation of a dose for a Phase 2 trial in patients. Results Currently, 12 patients have been treated and evaluated in the single dose groups of 0.25 mg, 2 mg, 10 mg and 30 mg (3 patients each). In the multiple dose group, 4 patients have been treated with 0.25 mg, 3 patients with 2 mg, 3 patients with 10 mg and 3 patients with 30 mg MGN1703, so far. Therapy was well tolerated except for sporadic transient symptoms as mild redness and induration of injection sites in two patients, increase of temperature to 38 °C in one patient, and fatigue in two patients. In the 0.25 mg group, one patient showed a stable disease (SD, according to RECIST) after 6 weeks of treatment, and in the 2 mg group, 3 of 3 patients showed a SD after 6 weeks. Treatment results of the last 2 dosing groups are pending. The four patients, who responded to the treatment with MGN1703, were treated with MGN1703 for further 6 weeks within an extension phase of this clinical trial. Two of them still had a SD after 12 weeks of treatment. Conclusions MGN1703 showed safety and tolerability at dosages up to 30 mg so far. The detailed evaluation of clinical and immunological responses is still ongoing. There has been no DLT at this point of the Phase 1 trial. Disclosures: Weihrauch: MOLOGEN AG: Membership on an entity's Board of Directors or advisory committees. Schmidt:MOLOGEN AG: Employment. Tschaika:MOLOGEN AG: Employment. Wittig:MOLOGEN AG: Membership on an entity's Board of Directors or advisory committees.