Abstract: 721 Background: Second-line Nal-Iri/5-Fluorouracil/Folinic Acid (Nal-Iri/5-FU/LV) increases overall survival of unselected patients (pts) with metastatic pancreatic ductal adenocarcinoma (PDAC) after gemcitabine-based therapy. It is unknown, which pts will likely benefit or could probably profit more from alternative approaches. Methods: In this prospective trial, 156 pts with locally advanced or metastatic PDAC were included for treatment with biweekly Nal-Iri/5-FU/LV (70 mg/m², 2.4 g/m², 400 mg/m²) after failure of 1st line chemotherapy with Gemcitabine/nab-Paclitaxel, with comprehensive evaluation of prior treatment characteristics, potential predictive factors, and quality of life. Primary end point is the correlation of time to treatment failure (TTF) of 1st and 2nd line therapy. Moreover, translational research was done to measure and evaluate biomarkers in blood and tumor tissue. Here, we explore patient characteristics in two subgroups with short or long treatment duration, with the aim to evaluate potential predictive factors for further analysis. Results: 139 (90%) of the 156 pts included between 03/2018 and 07/2021 in 40 German sites received medication. End of treatment is documented for 128 pts, with 5 still on treatment as of 05/2022 Mean (±SD) treatment duration was 15.5 weeks or 7.7±7.1 cycles (median 7 weeks; 5 cycles). 37 (25%) pts received ≥ 10 cycles. The median was used to separate two subgroups of short and long treatment duration (STD, ≤ 5 cycles, n=66 (52%) vs. LTD, 〉 5 cycles, n=62, (48%)). Reasons for treatment discontinuation clearly differed between the two subgroups: death in 9% vs. 3%, toxicity in 9% vs. 2%, unrelated medical condition in 12% vs. 2%, and progressive disease in 46% vs. 73%, respectively. Investigator´s decision was a reason for discontinuation in 6% vs. 5%. Pts with STD had a lower performance status (ECOG 1 or 2 in 74% vs. 52%, ECOG 0 in 20% vs. 44% in STD vs. LTD group), lower albumin levels (below normal in 36% vs. 24.2%) and were more likely to suffer from liver metastases (overall 82% vs. 66%). There were no relevant differences with regard to age, sex and tumor burden (number of metastases or CA19-9 levels). Conclusions: Early treatment discontinuation was primarily associated with patient-related factors such as low performance status, low albumin levels and comorbidities, characteristics which could be used to spare patients from treatment with an unfavorable risk-to-benefit ratio. In contrast, surrogate markers for tumor burden did not correlate with treatment success. Clinical trial information: NCT03468335 .

Abstract: e15607 Background: EVE (Afinitor) has demonstrated activity in the treatment of mRCC after failure of VEGF-targeted tyrosine kinase inhibitors. However, to this date, there is no published data evaluating its activity/safety after failure of first line BEV-based therapy. Methods: Our non-interventional multicenter international study reports retrospective data on EVE in routine use. Eligible patients had mRCC; were given EVE after 1 prior first-line systemic therapy with BEV +/- INF. The data were provided by each center and centralized. Results: Here are the final results: 20 sites included 43 pts between 2011 and 2012, with 42 evaluable patients. Baseline patient characteristics included median age of 69 [38-90] years old; 64.3% male; 97.5% with prior nephrectomy. First-line therapy was BEV + INF in 69% of patients, BEV only for 31%. Prognostic groups at the time of EVE initiation according to Heng (1) and to MSKCC (2) were respectively: (1): good 25%, intermediate 59.4% and poor prognosis 15.6% and (2) good 28.1%, intermediate 56.3% and poor 15.6%. Median duration of treatment with first line therapy was 7.5 months, and it was discontinuated for disease progression in 61.9 % of pts. From initiation of first line therapy 53.3 % of patients were alive at 32 months. Median OS was not reached for the second line; with 52.3% patients who had not progressed 8 months after the start of everolimus. Overall response rate was 9.5 % and disease stabilization rate was 50%. At least one adverse event (AE) occurred in 73.8 % of pts with 13 serious AEs. All grade common AEs were consistent with the toxicity profile of EVE with 31 % of stomatitis, 16.7 % of pneumonitis, 31 % of fatigue. Conclusions: This study provided encouraging results for the activity and safety profile of EVE in this second line mRCC setting after 1 prior first-line therapy with bevacizumab-based regimen. Further studies with larger numbers of pts are planned based on these novel findings.

Abstract: Ruxolitinib (RUX) is a Janus kinase 1/2 inhibitor (JAKi) approved in the EU for treating disease‑related splenomegaly or symptoms in adults patients with myelofibrosis (MF). This is an interim analysis of JAKoMo, a prospective, non‑interventional, phase IV study in MF. Between 2012–2019 (cutoff March 2021), 928 patients (JAKi-naïve and -pretreated) enrolled from 122 German centers. This analysis focuses on JAKi-naïve patients. RUX was administered according to the Summary of Product Characteristics. Compared to the COMFORT-I, -II, and JUMP trials, patients in JAKoMo were older (median 73 years), had poorer Eastern Cooperative Oncology Group (ECOG) performance statuses (16.5% had ECOG ≥ 2), and were more transfusion dependent (48.5%). JAKoMo represents the more challenging patients with MF encountered outside of interventional studies. However, patients with low-risk International Prognostic Scoring System (IPSS) scores or without palpable splenomegaly were also included. Following RUX treatment, 82.5% of patients experienced rapid (≤ 1 month), significant decreases in palpable spleen size, which remained durable for 24 months (60% patients). Symptom assessment scores improved significantly in Month 1 (median –5.2) up to Month 12 (–6.2). Common adverse events (AEs) were anemia (31.2%) and thrombocytopenia (28.6%). At cutoff, 54.3% of patients had terminated the study due to, death, AEs, or deterioration of health. No new safety signals were observed. Interim analysis of the JAKoMo study confirms RUX safety and efficacy in a representative cohort of real-world, elderly, JAKi-naïve patients with MF. Risk scores were used in less than half of the patients to initiate RUX treatment. Trial registration: NCT05044026; September 14, 2021.

Abstract: Background Panobinostat (Pano), a pan-histone deacetylase inhibitor, is approved for the treatment of relapsed or relapsed/refractory multiple myeloma (RRMM) in combination with bortezomib and dexamethasone (FVd) in patients who have received ≥2 prior lines of therapy, including bortezomib and an immunomodulatory agent (IMiD). The pivotal phase 3 PANORAMA 1 trial, which used intravenous (i.v.) bortezomib, demonstrated significant progression-free survival benefit with FVd compared with placebo-Vd; however, adverse events (AEs) were also more frequent (San-Miguel J. et al., Lancet Oncol. 2014). The randomized phase 2 PANORAMA 3 study was conducted to optimize FVd by comparing three regimens with varying dose and schedule of Pano and by incorporating subcutaneous (s.c.) bortezomib. Methods PANORAMA 3 (NCT02654990) was a randomized, open-label, international, multicenter phase 2 study conducted in compliance with the Declaration of Helsinki. Eligible patients were ≥18 years old with 1‒4 prior lines of therapy, including an IMiD. Patients refractory to bortezomib were excluded. Patients were randomized 1:1:1 to Pano 20 mg three times weekly (TIW; the currently approved dosing regimen; Days 1, 3, 5, 8, 10, 12), Pano 20 mg twice weekly (BIW; Days 1, 4, 8, 11), or Pano 10 mg TIW (Days 1, 3, 5, 8, 10, 12), all administered in 21-day cycles. Randomization was stratified by number of prior treatment lines (1 vs 2 vs 3 or 4) and by age at screening (≤75 vs & gt;75 years). For Cycles 1-4, all patients ≤75 years old received s.c. bortezomib 1.3 mg/m2 BIW (Days 1, 4, 8, 11) and oral dexamethasone 20 mg (Days 1, 2, 4, 5, 8, 9, 11, 12). Patients aged ≤75 years from Cycle 5 onwards, and patients & gt;75 years for all cycles, received bortezomib 1.3 mg/m2 weekly (Days 1 and 8) and dexamethasone 20 mg on Days 1, 2, 8, and 9. Patients were treated until progressive disease or death, or until discontinuation due to toxicity or withdrawal of consent. The primary endpoint was overall response rate (ORR; IMWG 2011 criteria) after up to 8 treatment cycles by Independent Review Committee assessment. Secondary endpoints included best response, time to response (TTR), duration of response (DOR) and safety. Results In total, 248 patients were randomized (Pano: 20 mg TIW, N=82; 20 mg BIW, N=83; 10 mg TIW, N=83) and 241 patients received treatment (Pano: 20 mg TIW, N=79; 20 mg BIW, N=82; 10 mg TIW, N=80). Mean (SD) age was 65 (9) years; 55% of patients were male. Overall, patients had a median (range) time since diagnosis of 49 months (7‒242) and a median (range) of 2 (1-4) prior lines of therapy; 17% and 2% of patients were refractory to lenalidomide and pomalidomide, respectively. In total, 68% of patients had relapsed and 32% had relapsed/refractory disease. High-risk molecular findings were present in 15% of patients, with either del(17p) or t (4;14) at screening by fluorescence in situ hybridization. For the Pano 20 mg TIW, 20 mg BIW, and 10 mg TIW arms, respectively, median (range) number of treatment cycles completed was 9 (1; 50), 8 (1; 40) and 7 (1; 39); ORR (95% CI) after up to 8 treatment cycles was 62% (51; 73), 65% (54; 75), and 51% (39; 62); median TTR was 1, 2, and 3 months, with a median (95% CI) DOR of 22 (14, not estimable), 12 (9, 21), and 11 (6, 14.5) months. Best responses are presented in Table 1. In the Pano 20 mg TIW, 20 mg BIW, and 10 mg TIW arms, respectively, treatment-related AEs Grade ≥3 were reported in 78%, 72%, and 54% of patients; serious AEs were reported in 54%, 48%, and 44% of patients; and discontinuations due to AEs occurred in 29.5%, 28%, and 15% of patients, respectively. Most common treatment-emergent AEs (≥20% patients) are presented in Table 2. Grade ≥3 diarrhea occurred in 11.5%, 10%, and 5% of patients, respectively. There were 14 (6%) on-treatment deaths during the study (20 mg TIW, n=5; 20 mg BIW, n=3; 10 mg TIW, n=6), with none causally related to therapy and with 12 of 14 directly attributable to progressive disease. Conclusion In patients with RRMM, the 20 mg TIW and 20 mg BIW dosing regimens provided favorable outcomes, with most durable and deepest responses observed in the 20 mg TIW arm. The rate of AEs, including diarrhea, with Pano 20 mg TIW was lower than those observed with the same dosing regimen in PANORAMA 1, suggesting s.c. administration of bortezomib improves tolerability compared with i.v. administration. Moreover, all three regimens of FVd proved generally manageable; Pano 20 mg TIW had greatest efficacy, while 10mg TIW proved best tolerated. Disclosures Schjesvold: Celgene, Amgen, Janssen, Oncopeptides: Research Funding; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, Takeda: Consultancy; Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, SkyliteDX, Takeda: Honoraria. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees. Lech-Marańda:Roche, Amgen, Gilead: Speakers Bureau; Roche, Novartis, Takeda, Janssen-Cilag, Amgen, Gilead, AbbVie, Sanofi: Consultancy. Spicka:Celgene, Amgen, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Novartis, Sanofi: Consultancy, Honoraria, Speakers Bureau. Hajek:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria; PharmaMar: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Oncopeptides: Consultancy. Wróbel:Roche: Honoraria, Research Funding; Takeda, Celgene, Janssen, Amgen, AbbVie, Teva, Sandoz: Consultancy, Honoraria. Sureda Balari:Takeda: Consultancy, Honoraria, Speakers Bureau; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Celgene: Consultancy, Honoraria; BMS: Speakers Bureau; Roche: Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria. Beksac:Janssen & janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Deva: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Goncalves:Janssen, Takeda, Amgen, Bayer, Novartis, Merck, Bayer, Celgene, GSK, BMS: Research Funding; Janssen: Consultancy, Speakers Bureau. Bladé Creixenti:Celgene: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Chari:Bristol Myers Squibb: Consultancy; Pharmacyclics: Research Funding; Novartis: Honoraria; Oncopeptides: Consultancy; Takeda: Consultancy, Research Funding; Antengene: Consultancy; Sanofi Genzyme: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Adaptive Biotechnology: Honoraria; Array BioPharma: Honoraria; Karyopharm: Consultancy; Glaxo Smith Kline: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; The Binding Site: Honoraria. Lonial:JUNO Therapeutics: Consultancy; Merck: Consultancy, Honoraria, Other: Personal fees; Abbvie: Consultancy; GSK: Consultancy, Honoraria, Other: Personal fees; BMS: Consultancy, Honoraria, Other: Personal fees, Research Funding; Janssen: Consultancy, Honoraria, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Takeda: Consultancy, Other: Personal fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Personal fees; Onyx: Honoraria; Genentech: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria. Spencer:Haemalogix: Consultancy, Honoraria, Other: Grant/Research Support; Secura Bio: Consultancy, Honoraria; Pharmamar: Other; Abbvie: Consultancy, Honoraria, Other: Grant/Research Support; Janssen: Consultancy, Honoraria, Other: Grant/Research Support, Speakers Bureau; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; TheraMyc: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Grant/Research Support; BMS: Honoraria, Other: Grant/Research Support, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Other: Grant/Research Support; Takeda: Honoraria, Other, Speakers Bureau; Antegene: Consultancy, Honoraria. Maison-Blanche:Chiesi Pharmaceutical, Sanofi, Novartis: Honoraria. Moreau:Novartis: Honoraria; Sanofi: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Richardson:Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. San-Miguel:Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract: 4008 Background: Chemotherapy (CT) is the standard of care in nonresectable locally advanced pancreatic cancer. The CONKO-007 trial studied the role of sequential CT and chemoradiotherapy (CRT). Methods: In this randomized multicenter phase III trial resectability was judged by an independent surgical board. Patients (pts) received induction chemotherapy (IC) for 3 months (3 cycles gemcitabine (Gem, 1000 mg/m² d1, 8, 15, q4w) or FOLFIRINOX (6 cycles, q2w)). After IC pts without progression were randomized to either continuing CT for another 3 months or receiving CRT (cumulative dose of 50.4Gy, single dose 1.8Gy + Gem 300 mg/m² weekly, followed by 1 cycle of Gem 1000 mg/m² at d1, 8, 15). The primary endpoint of the study was overall survival (OS) since the begin of IC. Determination of sample size calculated 590 pts to be randomized. Due to the exclusion of pts with progressive disease after IC a total of 830 pts should be enrolled. Due to delayed patient accrual the primary endpoint was changed to R0 resection rate resulting in an estimated sample size of 525 pts. Results: Between 04/2013 and 02/2021 a total of 525 pts were enrolled in 47 sites. 402 pts received IC with FOLFIRINOX and 93 pts with Gem. After IC 190 pts were excluded due to progression or toxicity, 335 were randomized, their median FU was 16 months. Hematological toxicities were significantly increased in the CRT arm, non-hematological toxicities were comparable. R0 CRM- resection rate and pCR rate was significantly higher in the CRT arm. R1-resections occurred significantly more often in the CT arm. Median progression-free survival (PFS) (HR 0.919, 95% CI 0.702-1.203, p=0.540) and OS (HR 0.964, 95% CI 0.760-1.225, p=0.766) did not differ significantly in both arms, whereas the PFS rate tended to be higher in the CRT arm after 2 years. OS rates for CRM- R0 surgery with 87.5. ± 0.05% (1y) and 67.2 ± 0.05% (2y) were significantly higher (p 〈 0.01) than for CRM+ R0 surgery with 66.7 ± 0.15% (1y) and 41.2 ± 0.1% (2y) as well as for patients without or incomplete surgery with 68.5 ± 0.03% (1y) and 26.4 ± 0.03% (2y). Conclusions: The addition of radiotherapy after IC improves the R0 CRM - resection and pCR rate without significant change in R0 resection rate (primary endpoint). Pts with R0 CRM - resections had a better prognosis compared to patients with either R0 CRM+ or incomplete or without surgery. However, this effect on resectability did not translate into a statistically significant PFS or OS benefit in the whole cohort. Clinical trial information: NCT01827553. [Table: see text]

Abstract: TPS4163 Background: The multi-targeted tyrosine kinase inhibitor cabozantinib is approved for the treatment of advanced hepatocellular carcinoma (HCC) in adults, who have previously been treated with sorafenib. In the pivotal phase 3 CELESTIAL trial a significant improvement for OS and PFS was shown for cabozantinib in comparison to placebo treated patients (Abou-Alfa GK et al. N Engl J Med 2018; 379:54-63). However, in 62% of patients a dose reduction of cabozantinib was necessary and the median average daily dose was 35.8 mg. The discontinuation rate due to treatment-related adverse events (TRAEs) was 16% and grade 3-4 TRAEs occurred in 68% of patients. For HCC patients treated with sorafenib in first-line, a reduced starting dose of 200 mg BID was not inferior in terms of OS but showed a trend toward a decreased rate of sorafenib discontinuation (Reiss KA et al. J Clin Oncol 2017; 35:3575-3581). The aim of the CaboRISE trial is to study the effect of a reduced starting dose of cabozantinib on tolerability, safety, and efficacy. Methods: The CaboRISE trial is an open-label, single arm, multicenter phase II trial, including patients with advanced stage hepatocellular carcinoma (HCC) with compensated liver cirrhosis (Child-Pugh A) in second line treatment, after first line treatment with sorafenib or lenvatinib. Forty evaluable patients will be enrolled in the study to receive a reduced starting dose of 40 mg cabozantinib once-daily for 4 weeks and subsequent dose escalation to 60 mg cabozantinib once-daily to be maintained until disease progression or intolerable toxicities. The objective of the trial is to assess the tolerability of a reduced starting dose of cabozantinib, in order to reduce the treatment discontinuation rates due to treatment-related adverse events below 10%. Primary endpoint is the treatment discontinuation rate due to TRAEs. Secondary endpoints are overall survival, progression free survival at 10 weeks, objective response rate, time on treatment, treatment exposure, toxicity, and quality of life. Study start of the CaboRISE trial was in October 2020. By February 2021, 7 centers across Germany have been initiated and a total of 4 out of 40 planned patients have been enrolled. The study is currently ongoing. This study is financially supported by Ipsen. ClinicalTrials.gov: NCT04522908 EudraCT: 2020-000775-20. Clinical trial information: NCT04522908.

Abstract: Erythropoiesis‐stimulating agents ( ESA s) remain first‐choice to treat symptomatic anemia and delay transfusion dependence in most patients with lower‐risk myelodysplastic syndromes ( MDS ) without del(5q). Deferasirox increased erythroid responses in some lower‐risk MDS patients in clinical trials, and adding low‐dose deferasirox to ESA treatment may further improve erythroid response. Methods KALLISTO ( NCT01868477 ) was a randomized, open‐label, multicenter, phase II study. Lower‐risk MDS patients received deferasirox at 10 mg/kg/d (dispersible tablets) or 7 mg/kg/d (film‐coated tablets) plus erythropoietin (n = 11), or erythropoietin alone (n = 12) for 24 weeks. The primary endpoint was the between‐group difference in erythroid response within 12 weeks. Results Erythroid response occurred in 27.3% of patients receiving deferasirox plus erythropoietin vs 41.7% of patients receiving erythropoietin alone within 12 weeks (difference 14.4%; 95% CI −24.0, 48.16). Within 24 weeks, the hematologic response rate was 27.3% with deferasirox plus erythropoietin vs 50% with erythropoietin alone, and hematologic improvement rates were 45.5% vs 100%. Deferasirox plus erythropoietin was generally well tolerated. Conclusions In this small pilot study, combining low‐dose deferasirox with erythropoietin did not improve erythroid response. It remains of interest to investigate early chelation approaches with even lower deferasirox doses plus erythropoietin in lower‐risk MDS patients before the onset of transfusion dependence.