Arm A1 Research Articles

A Phase Ib/II Randomized Clinical Trial of Oleclumab with or without Durvalumab plus Chemotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma upregulates CD73, potentially contributing to immune surveillance evasion. Combining oleclumab (CD73 inhibitor) and durvalumab with chemotherapy may identify an effective treatment option. We describe a multicenter phase Ib/II randomized clinical trial in patients with metastatic pancreatic ductal adenocarcinoma, untreated (cohort A) or previously received gemcitabine-based chemotherapy (cohort B; NCT03611556). During escalation, patients received oleclumab 1,500 or 3,000 mg, durvalumab 1,500 mg, and gemcitabine plus nab-paclitaxel (GnP; cohort A; n = 14) or modified FOLFOX (cohort B; n = 11). During expansion, cohort A patients (n = 170) were randomized to GnP (arm A1), oleclumab [recommended phase II dose (RP2D)] with GnP (arm A2), or oleclumab (RP2D) with durvalumab plus GnP (arm A3). Primary objectives were safety (escalation) and objective response rate (expansion). Secondary objectives included progression-free survival (PFS) and overall survival (OS). During escalation, 1/11 patients from cohort B (oleclumab 3,000 mg) experienced two dose-limiting toxicities. Oleclumab's RP2D was 3,000 mg. During expansion, grade ≥3 treatment-related adverse events occurred in 67.7% (42/62) of patients in A1, 73.7% (28/38) in A2, and 77.1% (54/70) in A3. The objective response rate was 29.0%, 21.1%, and 32.9% in A1, A2, and A3, respectively (A1 vs. A3; P = 0.650). PFS [HR = 0.72; 95% confidence interval (CI), 0.47, 1.11] and OS (HR = 0.75; 95% CI, 0.50-1.13) were similar for A3 versus A1. Patients with high CD73 expression had improved PFS and OS in A3 versus A1, although this should be interpreted with caution. Although the safety profile was acceptable, this study did not meet its primary efficacy endpoint.

Implementing fragmentomics into real world screening interventions to evaluate clinical utility among individuals with elevated risk for lung cancer (FIRSTLUNG) L301.

TPS11189 Background: To optimize the impact of lung cancer screening at the healthcare system level, additional tools are needed to increase the benefits of screening. While low-dose computed tomography (LDCT) has been shown to improve lung cancer detection and reduce mortality, it is not without its risks, such as radiation exposure, false-positive results, and unnecessary interventions often leading to complications. The additional complexity of lung cancer screening is the subpar adherence to LDCT for eligible individuals, which undermines the benefits of screening. Therefore, there is a need for alternative non-invasive methodologies that exploit our understanding of the biology of cancer pathogenesis. This clinical utility study aims to observe how a non–invasive blood-based test impacts physician behavior and LDCT utilization. Methods: FIRSTLUNG 301 (NCT06145750) is a prospective, cluster randomized controlled trial (RCT) to observe the impact of the DELFI Lung cancer screening test on lung cancer screening utilization in primary care practices. Enrolled practices must meet the eligibility criteria of having a minimum of 50 actively engaged individuals in the practice eligible for lung cancer screening per the 2021 USPSTF criteria. These practices will be randomized 1:1:2 to Arm A1 (control), Arm A2 (control), or Arm B (intervention). Arm A practices will be randomized 1:1 into two groups (A1:A2) to observe the standard of care for lung cancer screening. Practices in A1 will be observed; practices in A2 will receive standard education on lung cancer screening for CME credit. Randomizing within Arms A1 and A2 aims to delineate the impact standard lung cancer screening education may have on utilization. Arm B (intervention) practices will receive education and have access to order the blood-based test for screen-eligible individuals that remained unscreened. The primary study endpoint is the proportion of practice-identified lung cancer screen-eligible individuals receiving a screening CT order and scan during the study period in the entirety of Arm A (control) versus Arm B (intervention). This RCT aims to understand the utilization and impact on lung cancer screening uptake after the DELFI blood-based test intended to inform clinical guidelines and policies focused on improving patient care and health outcomes. Progress: The study was initiated on October 31, 2023, with practice randomization. As of February 2024, the study is open for enrollment with an estimated primary study completion date of December 2025. Clinical trial information: NCT06145750 .

Radiation dose esclation with contact X-ray brachytherapy (Papillon) and quality of life in patients with rectal cancer: Results from the phase 3 randomised trial OPERA.

e23180 Background: Organ preservation has been increasingly offered to patients with rectal cancer as most patients wish to avoid extirpative surgery and a stoma if they have a choice. The standard of care is to offer external beam chemo radiotherapy (EBCRT) to those who are fit. OPERA (Organ Preservation in Early Rectal Adenocarcinoma) has shown improved organ preservation rate with addition of contact X-ray brachytherapy(CXB-Arm B) compared to EBCRT with EBRT boost. We evaluate whether addition od CXB boost compromise the patients Quality of Life (QOL) compared to EBRT boost and if so by how much. We report our results at 38.2 months follow up. Methods: From June 2015 to June 2020, there were 148 patients randomised of which 141 were evaluable. We used EORCT QLQ -C30, QLQ -CR29 and modified LARS score at FU visits every 3 months during FU visit 1(8 weeks)-9 (32 weeks). Results: At screening (baseline) we enrolled 126 patients (Arm A: 59, Arm B: 66). At FU -1 we received questionnaire back from 78 patients (Arm A: 35, Arm B: 43). At FU-5 there were 55 patients (Arm A:18, Arm B: 37). Finally, at FU 8 there were 43 patients (Arm A: Arm B xx). Using EORTC QOL-C30 and QOL CR-29, global QOL score for Arm A was 77.6 vs Arm B 72.22 (p = 0.14). Mean functional scale (1-5) for Arm A was 95.2 vs Arm B 92.1 (p = 0.09). Role functioning scale (6-7) for Arm A was 91.2 vs Arm B 93.18 (p = 0.57). Emotional functioning (21-24) for Arm A was 77.5 vs Arm B 73.99 (p = 0.33). Cognitive functioning (20-25) for Arm A 87.85 vs Arm B 91.92(p = 0.17). Social functioning (26-27) for Arm A 95.2 vs Arm B 92.93 (p = 0.31). Conclusions: In our analysis so far, we do not detect significant difference in QOL between Arm A and Arm B. Consider Contact x-ray brachytherapy first in patients with rectal cancer < 3cm (Arm B1) which has shown higher organ preservation rate without effecting their QOL compare to EBCRT (Arm A1). Clinical trial information: NCT02505750 .

EDGE-Gastric Arm A1: Phase 2 study of domvanalimab, zimberelimab, and FOLFOX in first-line (1L) advanced gastroesophageal cancer.

433248 Background: The addition of programmed cell death protein 1 (PD-1) inhibitors to chemotherapy (chemo) confers a survival advantage in 1L gastroesophageal cancers. However, long term outcomes remain poor. Dual PD-1 and anti-T-cell immunoglobulin and ITM domain (TIGIT) blockade increases tumor antigen-specific CD8+ T cell expansion, resulting in potent antitumor activity. The ongoing, multi-arm, global EDGE-Gastric trial (NCT05329766) is evaluating the safety and efficacy of various combinations of the anti-TIGIT Fc-silent monoclonal antibody (mAb) domvanalimab (D) and the anti-PD-1 mAb zimberelimab (Z) in patients (pts) with locally advanced unresectable or metastatic gastric (G)/gastroesophageal junction (GEJ)/esophageal (E) adenocarcinoma. Arm A1 is fully enrolled and results from this 1L arm are presented here. Methods: Patients with previously untreated G/GEJ/E adenocarcinoma received D 1600 mg intravenously (IV) every 4 weeks (Q4W) + Z 480 mg IV Q4W + FOLFOX (oxaliplatin 85 mg/m2 IV, leucovorin 400 mg/m2 IV, fluorouracil 400 mg/m2 IV bolus + 2400 mg/m2 continuous 46-48-hour IV infusion) Q2W. Primary endpoints are safety and objective response rate (ORR) per RECIST 1.1. Secondary endpoints include ORR by PD-L1 expression and PFS. Results: As of the data cutoff (5 June 2023), 41 pts were enrolled and had the opportunity to have ≥2 imaging assessments. There was an even distribution of pts accrued in Asia vs. rest of world and 63% of pts had gastric cancer. Median time on treatment was 23 weeks (1 to 40), 31 pts (76%) continue on protocol therapy, and there were no deaths on study. Intent-to-treat ORR was 59% (95% CI 42 to 74). Clinical outcomes by PD-L1 status are in the Table. The most common treatment-emergent adverse events (TEAE) were neutropenia (56% of pts), nausea (54%), and anemia (27%). Infusion related reactions were observed in 10% and none were deemed related to D/Z. Grade ≥3 TEAEs occurred in 66% pts, with 54% and 12% having grade ≥3 TEAEs related to FOLFOX and D/Z, respectively. Serious TEAEs occurred in 24% pts: 7% had serious TEAEs related to FOLFOX and no pts had serious TEAEs related to D/Z. TEAE related FOLFOX discontinuation occurred in 13 pts (32%), and in 1 pt due to D/Z. Conclusions: Addition of DZ to FOLFOX showed encouraging ORR and early PFS, particularly in pts with PD-L1-high tumors. The regimen is well tolerated, with a similar AE profile to anti-PD-1+FOLFOX. Updated safety and efficacy will be presented. The randomized phase 3 1L STAR-221 trial of DZ+chemo vs. SOC is underway. Clinical trial information: NCT05329766 . [Table: see text]

Safety and clinical activity of oleclumab (O) ± durvalumab (D) + chemotherapy (CT) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC): A phase 1b/2 randomized study.

4136 Background: In a phase 1 study, the anti-CD73 monoclonal antibody (mAb) O plus the anti-PD-L1 mAb D showed antitumor activity and manageable safety in previously treated pts with advanced PDAC (Overman et al, J Clin Oncol 2018;36[suppl 15]:abs 4123). Here we report a multicenter, open-label study of O ± D + CT in pts with mPDAC. Methods: Pts were ≥18 years old with ECOG PS 0–1. Part 1 was a dose escalation phase: in Cohort A, previously untreated (1L) pts received O 1500 or 3000 mg IV Q2W for 4 doses then Q4W + D 1500 mg IV Q4W, with Q4W gemcitabine and nab-paclitaxel (GnP). In Cohort B, pts with previous G-based CT (2L) received O 1500 or 3000 mg Q2W for 4 doses then Q4W + D 1500 mg Q4W, with Q4W mFOLFOX. The primary objective for Part 1 was safety and tolerability; secondary objectives included antitumor activity and pharmacokinetics (PK). Part 2 was an expansion phase in which pts were stratified by high/low tumoral CD73 expression by IHC. In Cohort A, 1L pts were randomized 1:1:1 to GnP alone (Arm A1), O + GnP (Arm A2) or O + D + GnP (Arm A3). O was given at the recommended phase 2 dose, 3000 mg. Cohort B did not proceed to dose expansion due to emerging therapies in 2L PDAC pts. The primary endpoint for Part 2 was investigator-assessed objective response rate (ORR) by RECIST v1.1; secondary included PFS, OS, safety, PK and antidrug antibody data. Results: As of November 11, 2022, 25 pts were treated in Part 1 (Cohort A, n=14; Cohort B, n=11), and 170 pts were treated in Part 2 (Arm A1, n=62; Arm A2, n=38; Arm A3, n=70). In Part 1, dose-limiting toxicities occurred in 1 pt (Cohort B, O 3000 mg: Gr 3 nausea and Gr 3 localized edema). Safety was generally similar in Parts 1 and 2. In Part 2, Gr ≥3 treatment-emergent adverse events (TEAEs) occurred in 85.5%, 89.5% and 90.0% of pts in Arms A1, A2 and A3 respectively, most commonly neutropenia (22.6%, 34.2% and 17.1%). In Part 2, TEAEs led to discontinuation in 11.3%, 23.7% and 24.3% of pts respectively. In Part 2, ORR was similar across Arms with a trend toward longer PFS and OS in Arm 3 vs Arm 1. There was a trend toward greater clinical benefit in pts with high CD73 expression when comparing Arm A3 vs Arm A1. Conclusions: O + D + GnP had similar safety and a trend toward improved outcomes compared to GnP. Clinical trial information: NCT03611556 . [Table: see text]

Modified FOLFOX plus/minus nivolumab and ipilimumab vs FLOT plus nivolumab in patients with previously untreated advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction: The randomized phase 2 IKF-S628 Moonlight trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

4050 Background: FOLFOX plus nivolumab has become standard of care for first-line therapy of patients (pts) with esophagogastric adenocarcinomas (EGA). The AIO-STO-0417 trial (Moonlight) is a multi-cohort treatment optimization trial that evaluates the combination of FOLFOX alone (Arm B) vs FOLFOX plus nivolumab (nivo) and ipilimumab (ipi) administered in parallel (Arm A/A1) or sequentially (Arm A2) and FLOT plus nivolumab administered in parallel (Arm C) for 1L-treatment of metastatic or advanced inoperable Her-2 negative EGA. The aim is to generate signals whether a. dual checkpoint inhibition or b. a triplet chemotherapy is beneficial in the context of nivolumab therapy for this disease. Methods: Pts were randomized 1:1 to Arm A (mFOLFOX q2w plus nivo 240 mg q2w + ipi 1 mg/kg q6w administered in parallel) or B (mFOLFOX alone). In a subsequent phase pts were randomized 1:2 to Arm A1 (identical to Arm A) or A2 (three cycles of mFOLFOX followed by nivo q2w + ipi q6w, with optional repetition). In a final phase, all pts were allocated to single Arm C (FLOT q2w + nivo q2w). The primary endpoint was progression-free survival (PFS) based on the ITT population for Arm A vs Arm B and PFS rate at 6 months (PFS@6) for Arms A2 and C. Main secondary endpoints were PFS and ORR. Here, we present results for Arms A/A1, A2 and B. Results: A total of 262 pts were enrolled, Arm A (n=60), Arm B (n=60), Arm A1 (n=30), Arm A2 (n=60) and Arm C (n=52, results presented elsewhere). Baseline characteristics were comparable in all arms. Overall PD-L1 expression (CPS ≥1) was low with 41% and balanced between Arms A/A1, A2 and B. Analysis of pooled Arms A/A1 (n=90) showed an increase in toxicity (pts with AEs grade ≥3 88% vs 65% in Arm B and 75% in Arm A2, treatment related SAEs grade ≥3 A/A1 41% vs B 18% vs A2 17%) but not in activity. Arm A/A1 compared with Arm A2 was more effective in terms of PFS@6 (48% vs 30%), median PFS 5.8 vs 4.0 months and objective response rate (ORR) 46% vs 30%. Conclusions: Albeit the small number of pts in each cohort we conclude that in the first-line setting of metastatic EGA. a) Chemo plus dual checkpoint inhibition administered in parallel is associated with an increase in toxicity but not activity. b) Although associated with lower toxicity the use of sequential chemo followed by IO monotherapy is insufficient. The relatively low numbers of patients with PD-L1 CPS ≥1 may have impacted these results. Clinical trial information: NCT03647969 .

A phase 1/2 study of CFT1946, a novel, bifunctional degradation activating compound (BIDAC) degrader, of mutant BRAF V600 as monotherapy and in combination with trametinib, in mutant BRAF V600 solid tumors.

TPS3163 Background: BRAF is a protein kinase that acts as a signal transducer in the MAPK pathway. Mutant BRAF V600 is capable of uncontrolled signaling and is constitutively active and signals as a monomer, leading to hyperactivation of MEK, ERK, and dysregulation of cellular proliferation. Mutant BRAF V600 is a clinically-validated target in a variety of cancers including melanoma, colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and anaplastic thyroid carcinoma (ATC). Currently approved BRAF inhibitors (BRAFi) result in paradoxical RAF activation as the mutant BRAF protein is still able to dimerize with WT BRAF, resulting in a dimeric signaling complex. CFT1946 is a novel, orally bioavailable BiDAC degrader that inhibits and degrades mutant BRAF V600 protein. Distinct from approved BRAFi, CFT1946 avoids paradoxical RAF activation as the degraded BRAF V600 mutant protein can no longer incorporate into a dimeric signaling complex. CFT1946 is selective for the mutant protein and spares WT BRAF V600. CFT1946 has demonstrated preclinical activity in BRAF V600 mutant in vitro and in vivo models, including models resistant to BRAFi. These preclinical data provide rationale for a first-in-human (FIH) study to evaluate CFT1946 in BRAF V600 mutant solid tumors. Methods: This is a FIH, open-label, multicenter, Phase 1/2 clinical trial to characterize the initial safety, tolerability, and preliminary efficacy of CFT1946 and CFT1946+trametinib in BRAF V600 mutant melanoma, NSCLC, CRC, ATC, and other non-CNS BRAF V600 mutant solid tumors. This study includes 2 phases: dose escalation Phase 1 comprising CFT1946 (Arm A) with a starting oral dose of 20 mg twice daily and CFT1946+trametinib (Arm B) as well as dose expansion Phase 2 comprising CFT1946 (Arm A1) and CFT1946+trametinib (Arms B1 and B2). Arm A1 and B1 will include BRAF V600 mutant melanoma and NSCLC with prior BRAFi therapy while Arm B2 will enroll BRAF V600 mutant NSCLC who are BRAFi-naïve. Phase 2 will be initiated once the RP2D has been identified. Eligible subjects are ≥18yo with documented BRAF V600 mutant cancers who have received ≥1 prior therapy. CFT1946 will be administered orally in 28-day cycles until disease progression or intolerable toxicity. Primary objectives include safety, tolerability, RP2D and preliminary antitumor activity of CFT1946 monotherapy and in combination with trametinib. Secondary objectives include assessment of pharmacokinetics and pharmacodynamics. Key inclusion criteria include documented evidence of a BRAF V600 mutation obtained from tumor tissue or liquid biopsy; at least 1 prior line of standard-of-care therapy for locally advanced or metastatic disease. The study is anticipated to enroll 101-122 patients across 11 participating US and European sites and is currently open to enrollment (NCT05668585). Clinical trial information: NCT05668585 .

A phase 3 trial of fianlimab (anti–LAG-3) plus cemiplimab (anti–PD-1) versus pembrolizumab in patients with previously untreated unresectable locally advanced or metastatic melanoma.

TPS9602 Background: Fianlimab (anti-lymphocyte activation gene 3 [LAG-3]) and cemiplimab (anti- programmed cell death-1 [PD-1]) are both high-affinity, fully human, IgG4 monoclonal antibodies (Abs). Concurrent blockade of anti-LAG-3 and anti-PD-1 has shown enhanced efficacy (increase in progression free survival [PFS]) in advanced melanoma (Mel). We previously presented data from a phase 1 study showing a 63.8% objective response rate (ORR) across two separate cohorts of advanced PD-(L)1 naïve metastatic Mel patients (pts) treated with fianlimab plus cemiplimab with an acceptable risk-benefit profile. Methods: This is a randomized, double-blind, phase 3 study to evaluate fianlimab plus cemiplimab compared to pembrolizumab in pts with previously untreated unresectable locally advanced or metastatic Mel (NCT05352672). This study will be conducted globally, at approximately 200 sites. Key inclusion criteria are: (1) ≥12 years of age; (2) histologically confirmed unresectable Stage III and Stage IV (metastatic) Mel (3) no prior systemic therapy for advanced unresectable disease, prior (neo)adjuvant therapies are allowed with treatment/disease-free interval of 6 months; (4) measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1; (5) valid LAG-3 results; (6) Eastern Cooperative Oncology Group performance status (PS) of 0 or 1 (for adult pts), Karnofsky PS ≥70 (pts ≥16 years) or Lansky PS ≥70 (pts < 16 years); and (7) anticipated life expectancy of at least 3 months. There are 4 arms to the study: (1) Arm A: fianlimab (1600 mg) + cemiplimab (350 mg) every 3 weeks (Q3W), intravenously (IV); (2) Arm A1: fianlimab (400 mg) + cemiplimab (350 mg) Q3W, IV; (3) Arm B: pembrolizumab (200 mg Q3W, IV) + saline/dextrose placebo (placebo); (4) Arm C: cemiplimab (350 mg Q3W, IV) + placebo. The trial is expected to enroll approximately 1590 pts. The primary endpoint is progression-free survival. The key secondary endpoints are overall survival and objective response rate. The additional secondary endpoints include disease control rate, duration of response, safety, pharmacokinetics of cemiplimab and fianlimab, and immunogenicity (incidence and titer of anti-drug Abs and neutralizing Abs). The study is currently open for enrollment. Clinical trial information: NCT05352672 .

Long-Term Outcome of a Prospective Randomized Trial Comparing Continuous Lenalidomide/Dexamethasone with Lenalidomide/Dexamethasone Induction, MEL140 with Autologous Blood Stem Cell Transplantation and Single Agent Lenalidomide Maintenance in Patients of Age 60-75 Years with Newly Diagnosed Multiple Myeloma

Background: Lenalidomide/dexamethasone has been approved as a standard treatment in multiple myeloma and is applied preferentially in older patients with comorbidities. The addition of daratumumab to this therapy is the best treatment option today for patients who are not transplant eligible. Intensity-reduced high-dose melphalan (MEL140) with autologous transplantation also is an effective treatment option for older patients who are transplant eligible but may not tolerate full dose high-dose melphalan (MEL200). A combination of MEL140 with lenalidomide/dexamethasone potentially could produce a better outcome compared with lenalidomide/dexamethasone alone. Methods: In this trial (DSMM XIII; EudraCT-No: 2008-004083-39) patients of age 60-75 years with newly diagnosed multiple myeloma who had symptomatic and measurable disease were randomly assigned to either (A1) 3 cycles of lenalidomide (25 mg po d1-21/28d) with low-dose dexamethasone (40 mg po d1, d8, d15, d22/28d), followed by stem cell mobilization and then further lenalidomide/dexamethasone cycles until progression or (A2) 3 cycles of lenalidomide/dexamethasone as induction, followed by stem cell mobilization, intensity-reduced high-dose melphalan 140 mg/m2 (MEL140) (single or double) with autologous blood stem cell transplantation and lenalidomide maintenance with 10 mg daily until progression. At randomization, patients were stratified according to age (60-70 years vs 71-75 years) and ISS stage (I, II vs III). The primary endpoint was progression-free survival, and secondary endpoints included safety, response rates and overall survival. Here, we report the long-term outcome. Results: 348 patients were included into the study and 339 patients could be analysed per intention-to-treat (ITT). Patient characteristics were well balanced between treatment arms. For all patients, median age was 68 years (range 60 - 75), 29% were older than 70 years, 36.5% had ISS stage I, 35.6% ISS stage II, and 27.9% ISS stage III. After a median follow-up of 68 months, the median progression-free survival (PFS) was 40 months for A1 (169 patients) and 33 months for A2 (170 patients) (HR 1.16; p=0.19) in the ITT analysis. The median overall survival (OS) was 87 months for A1 and 96 months for A2 (HR 1.04; p=0.81). A prespecified per-protocol (PP) analysis was defined to include patients who received at least 6 months of study treatment (also including patients with progressive disease or death during this time period). In this PP analysis the median PFS was 42 months for A1 (139 patients) and 36 months for A2 (131 patients) (HR 1.15; p=0.27); the median OS was 89 months for A1 and 96 months for A2 (HR 1.01; p=0.96). In arm A2, 115 patients (68%) received one or two transplants. For transplanted patients, median PFS was 40 months and median OS was 114 months. Second primary malignancies (SPMs) were observed in 24 patients in arm A1 (skin 12, solid tumor 11, hematologic 1) and in 20 patients in arm A2 (skin 5, solid tumor 11, hematologic 4). Conclusion: In the intention-to-treat population, the combination of MEL140 with lenalidomide/dexamethasone induction and lenalidomide single agent maintenance was not superior to continuous lenalidomide/dexamethasone treatment. Subgroup analyses with a focus on the role of transplant will be presented at the meeting. Sponsor: Gesellschaft für Medizinische Innovation in der Hämatologie/Onkologie - GMIHO

1203O FOLFOX plus nivolumab and ipilimumab versus FOLFOX induction followed by nivolumab and ipilimumab in patients with previously untreated advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction: Results from the randomized phase II Moonlight trial of the AIO

FOLFOX plus nivolumab (nivo) has become standard of care for first-line therapy of patients (pts) with esophagogastric adenocarcinomas. To reduce toxicity, there is a need to evaluate if short-term induction chemotherapy followed by immunotherapy as an alternating treatment is as effective, while more tolerable. The aim of this second part of the Moonlight trial was to evaluate if mFOLFOX induction therapy followed by nivo plus ipilimumab (ipi) is less toxic but equally effective compared to both regimens combined together. Results of the other study parts will be presented elsewhere. The AIO-STO-0417 trial (Moonlight) is a four-arm investigator-initiated trial, whereof two arms (A1/A2) are presented here. Pts were randomized 1:2 to FOLFOX plus nivo 240 mg; q2w and ipi 1 mg/kg; q6w administered in parallel (arm A1; parallel treatment) or three cycles of mFOLFOX induction treatment followed by nivo and ipi (arm A2; sequential treatment). PD-L1 expression was centrally assessed. Primary endpoint was progression-free survival at 6 months ([email protected]), main secondary endpoints were OS, PFS, objective response rate (ORR) and safety. Ninety patients were randomized (30 pts to arm A1 and 60 pts to A2). Baseline characteristics were: median age 62y, GEJ, 51%, intestinal type, 33%. Forty-one percent had PD-L1 CPS≥1 (available in 74% of pts). Pts received a median of 11 cycles in A1 vs 7 cycles in A2. Adverse events of grade ≥3 were seen in 93% of the pts for arm A1 and 73% for arm A2, serious adverse events (SAE) in 70% in arm A1 and 62% in A2. Median follow-up was 7.3 mo. [email protected] was 57% in arm A1 vs 28% in A2 (p=.012) with median PFS 8.4 vs 4.0 mo, respectively (p=.006). Median OS was not yet reached in A1 vs 9.1 mo in A2, ORR was 47% vs 30%, respectively. The results were similar in the PD-L1+ group. FOLFOX chemotherapy plus nivolumab and ipilimumab administered in parallel was clearly more effective than FOLFOX induction followed by nivo and ipi. Although associated with lower toxicity, our study doesn’t support the use of sequential treatment in the first-line setting.

FOLFOX versus FOLFOX plus nivolumab and ipilimumab administered in parallel or sequentially versus FLOT plus nivolumab administered in parallel in patients with previously untreated advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction: A randomized phase 2 trial of the AIO.

4043 Background: FOLFOX plus nivolumab (nivo) has become standard of care for first-line therapy of patients (pts) with esophagogastric adenocarcinomas. The aim of Moonlight trial is to generate signals for whether (a) dual checkpoint inhibition or (b) a triplet chemotherapy is beneficial in the context of nivolumab therapy in this setting. Methods: The AIO-STO-0417 trial (Moonlight) is a four-arm investigator-initiated trial. Pts were randomized to FOLFOX alone (Arm B) or FOLFOX plus nivo 240 mg; q2w and ipilimumab (ipi) 1 mg/kg; q6w administered in parallel (Arm A/A1) or sequentially (Arm A2) or pts were treated in a non-randomized fashion with FLOT plus nivo 240 mg; q2w (Arm C). PD-L1 expression was centrally assessed. Primary endpoint is progression-free survival (PFS). Results: The study completed enrollment with 260 pts. Arms A1/A2 and C started later and will be analyzed in Mar 2022 and presented at the meeting. The abstract, therefore, focuses on Arms A (n = 60) vs B (n = 60). Baseline characteristics were: median age 62.5y, GEJ, 55%, intestinal type, 36%. Forty-one percent had PD-L1 CPS≥1 (available in 79% of pts). Pts received a median of 10 and 9 cycles Arms A and B. Adverse events of grade 3/4 were seen in 86% for Arm A and 60% for Arm B, respectively, and serious adverse events (SAE) in 78% in Arm A and 50% in Arm B. Median follow-up was 9.7 mo. No difference in PFS (5.7 and 6.6 mo), OS (10 vs. 12 mo) or objective response rate (45% and 48%) was seen in Arms A and B, respectively. The results were similar in the PD-L1+ group. Conclusions: FOLFOX plus dual checkpoint inhibition administered in parallel is associated with an increase in toxicity but not activity. This portion of the moonlight trial does not generate a signal for further trials on FOLFOX plus nivo and ipi for adenocarcinoma of stomach and GEJ. Clinical trial information: NCT03647969.

Elotuzumab in Combination with Lenalidomide, Bortezomib, Dexamethasone and Autologous Transplantation for Newly-Diagnosed Multiple Myeloma: Results from the Randomized Phase III GMMG-HD6 Trial

Elotuzumab in Combination with Lenalidomide, Bortezomib, Dexamethasone and Autologous Transplantation for Newly-Diagnosed Multiple Myeloma: Results from the Randomized Phase III GMMG-HD6 Trial

Response-Adapted Lenalidomide Maintenance in Newly Diagnosed, Transplant-Eligible Multiple Myeloma: Results from the Multicenter Phase III GMMG-MM5 Trial

Response-Adapted Lenalidomide Maintenance in Newly Diagnosed, Transplant-Eligible Multiple Myeloma: Results from the Multicenter Phase III GMMG-MM5 Trial

P188 Secukinumab provides significant improvement of spinal pain and lowers disease activity in patients with axial spondyloarthritis: 24-week results from a randomised controlled Phase 3b trial

Abstract Background/Aims SKIPPAIN (NCT03136861) is the first randomised controlled study involving a biological disease-modifying anti-rheumatic drug, with a primary endpoint of spinal pain at Week 8 in patients with axial spondyloarthritis (axSpA; ankylosing spondylitis [AS] and non-radiographic [nr]-axSpA). We present the 24-week results of secukinumab in reducing spinal pain and disease activity following step-up dosing. Methods This double-blind, placebo-controlled Phase 3b study enrolled patients (aged ≥18 years) with active disease (BASDAI ≥4; average spinal pain numerical rating scale [NRS] score >4 at baseline; inadequate response to ≥ 2 non-steroidal anti-inflammatory drugs ≥4 weeks). Patients were randomised (3:1) to subcutaneous secukinumab 150 mg or placebo weekly followed by every 4 weeks (Q4W) from Week 4. At Week 8, placebo patients were re-randomised to secukinumab 150 or 300 mg Q4W. Patients originally randomised to secukinumab 150 mg were classified as responders or non-responders (spinal pain NRS score <4 or ≥ 4, respectively) at Week 8. Responders were re-assigned to continue doubleblind secukinumab 150 mg Q4W (Arm A1). Non-responders were re-randomised to double-blind secukinumab 150 mg (Arm A2) or a step-up dose of 300 mg (Arm A3) Q4W. Treatment was up to Week 24. Primary endpoint: proportion of patients achieving an average spinal pain score <4 on a 0-10 NRS with secukinumab vs placebo at Week 8. Results 380 axSpA patients (269/380 [70.8%] AS; 111/380 [29.2%] nr-axSpA) were randomised to secukinumab 150 mg (N = 285) or placebo (N = 95). The primary endpoint was met (proportion of spinal pain NRS [average] score responders: 32% vs 20%; odds ratio [95% confidence interval] 1.9 [1.1-3.3] favouring secukinumab vs placebo; P < 0.05). Further reductions in spinal pain occurred at Week 24, especially in those initially randomised to placebo and switched to active drug. Pronounced improvements were observed in other disease activity measurements (Table 1). Numerically, more patients achieved ASDAS low disease activity at Week 24 post-secukinumab dose escalation (Arm A3) vs those remaining on the same dose (Arm A2). Conclusion Secukinumab provided rapid, significant improvement in spinal pain and led to low disease activity in axSpA patients. Secukinumab dose escalation might be beneficial for patients not responding fully to the starting dose. P188 Table 1:Spinal pain and ASDAS-CRP scores at Weeks 8 and 24Week 8SEC 150 mg (N = 285)PBO (N = 95)Change from baseline in spinal pain NRS score (total), mean (SD) [n]-2.6 (2.5) [279]-1.5 (2.2) [92]Change from baseline in ASDAS-CRP score, mean (SD) [n]-1.2 (1.0) [271]-0.5 (0.8) [89]Week 24Active treatment group (SEC treatment starting at baseline)PBO switchers group (SEC treatment starting at Week 8)Arm A1 (SEC 150 R-150) N = 90Arm A2 (SEC 150 NR-150) N = 94Arm A3 (SEC 150 NR-300) N = 94Arm B1 (PBO-SEC 150) N = 45Arm B2 (PBO-SEC 300) N = 44Change from Week 8 in spinal pain NRS score (total), mean (SD) [n]-0.4 (1.5) [88]-2.1 (2.2) [93]-1.9 (2.2) [91]-2.5 (2.6) [45]-2.9 (2.6) [43]Change from baseline in ASDAS-CRP score, mean (SD) [n]-2.2 (1.0) [86]-1.2 (1.0) [93]-1.5 (1.0) [92]-1.5 (1.1) [44]-1.8 (0.9) [43]Arm A1=SEC responder to SEC 150 mg at Week 8 (SEC 150 R-150); Arm A2=SEC non-responder to SEC 150 mg at Week 8 (SEC 150 NR-150); Arm A3=SEC non-responder to SEC 300 mg at Week 8 (SEC 150 NR-300); Arm B1=Placebo patients to SEC 150 mg (PBO-SEC 150); Arm B2=Placebo patients to SEC 300 mg (PBO-SEC 300). ASDAS-CRP, Ankylosing Spondylitis Disease Activity Score using C-reactive protein; N, total number of patients randomised; n, number of evaluable patients; NR, non-responders; NRS, numerical rating scale; PBO, placebo; R, responders; SD, standard deviation; SEC, secukinumab. Disclosure H. Marzo-Ortega: Consultancies; AbbVie, Celgene, Janssen, Lilly, Novartis, Pfizer, UCB. Member of speakers’ bureau; AbbVie, Celgene, Janssen, Lilly, Novartis, Pfizer, Takeda, UCB. Grants/research support; Janssen, Novartis. C. Perella: Corporate appointments; Employee of Novartis. Shareholder/stock ownership; Novartis Stock. D. Poddubnyy: Consultancies; Consultant/speaker for: AbbVie, BMS, Lilly, MSD, Novartis, Pfizer, Roche, UCB. Grants/research support; AbbVie, MSD, Novartis, Pfizer. E. Pournara: Corporate appointments; Employee of Novartis. Shareholder/stock ownership; Novartis Stock. A. Zielińska: Consultancies; Novartis, Pfizer. A. Baranauskaite: Consultancies; AbbVie. Member of speakers’ bureau; Novartis, AbbVie, Amgen, Roche, KRKA. S. Sadhu: Corporate appointments; Employee of Novartis. B. Schulz: Corporate appointments; Employee of Novartis. M. Rissler: Corporate appointments; Employee of Novartis. Shareholder/stock ownership; Novartis Stock.

Impact of Annual Albendazole versus Four-Monthly Test-and-Treat Approach of Intestinal Parasites on Children Growth-A Longitudinal Four-Arm Randomized Parallel Trial during Two Years of a Community Follow-Up in Bengo, Angola.

Malnutrition and intestinal parasites continue to have serious impacts on growth and cognitive development of children in Angola. A longitudinal four-arm randomized parallel trial was conducted to investigate if deworming with a single annual dose of albendazole (annual-ALB) or a four-monthly test-and-treat (4TT) intestinal parasites approach at individual or household levels improve nutritional outcomes of pre-school children in Bengo province. Children with intestinal parasites (n = 121) were randomly assigned (1:1:1:1) to arm A1: annual-ALB*individual level; A2: annual-ALB*household level; A3: 4TT*individual; and A4: 4TT*household level. At baseline, 4, 8, 12, 16, 20, and 24 months of follow-up, growth was assessed by height, weight, height-for-age, weight-for-height, weight-for-age, and mid-upper arm circumference. Intention-to-treat analysis was done using non-parametric approach, mixed effect models, and generalized estimating equations (GEE). Initially, 57% and 26% of the children were infected by Giardia lamblia and Ascaris lumbricoides, respectively. This study did not show that a 4TT intestinal parasites approach results on better growth outcomes of children (height, weight, HAZ, WAZ, WHZ and MUACZ) when compared with annual ALB, with exception of height and WHZ using GEE model at 5% level. Positive temporal effects on most nutrition outcomes were observed. Implementing a longitudinal study in a poor setting is challenging and larger sample sizes and ‘pure and clean’ data are difficult to obtain. Nevertheless, learned lessons from this intensive study may contribute to future scientific research and to tailor multidisciplinary approaches to minimize malnutrition and infections in resource-poor countries.

Rapid improvement in spinal pain in patients with axial spondyloarthritis treated with secukinumab: primary results from a randomized controlled phase-IIIb trial.

Background:This study aimed to evaluate the efficacy and safety of secukinumab 150 mg compared with placebo in the management of spinal pain and disease activity in patients with axial spondyloarthritis (axSpA) at Week 8 and up to Week 24.Methods:Patients (n = 380) with active axSpA were randomized (3:1) to secukinumab 150 mg (Group A) or placebo (Group B). At Week 8, patients from Group A with an average spinal pain score <4 were defined as responders and were re-assigned to secukinumab 150 mg (Arm A1); whereas non-responders were re-randomized to secukinumab 150/300 mg (Arm A2/A3). Patients from Group B were re-randomized (1:1) to secukinumab 150/300 mg (Arm B1/B2).Results:At Week 8, the odds of achieving an average spinal pain score of <4 were significantly higher for patients on secukinumab 150 mg than for patients on placebo (odds ratio (OR): 1.89; 95% confidence interval (CI): 1.08–3.33; p = 0.0264). Further reductions in spinal pain were observed across treatment groups up to Week 24. Pronounced improvements were also observed in other disease activity measurements, such as Bath Ankylosing Spondylitis Disease Activity Index and Ankylosing Spondylitis Disease Activity Score. Responders from Group A showed the highest improvements for all measured parameters of spinal pain compared with the other arms. No new or unexpected safety signals were observed.Conclusion:Secukinumab provided rapid and significant improvement in spinal pain at Week 8 which was sustained or increased further up to Week 24 in patients with axSpA.Trial Registration:ClinicalTrials.gov: NCT03136861. Registered May 2, 2017.

Bortezomib, lenalidomide, and dexamethasone (VRD) is superior to lenalidomide, adriamycin, and dexamethasone (RAD) prior to risk-adapted transplant in newly diagnosed myeloma.

8521 Background: High-dose chemotherapy (HDT) followed by autologous stem cell transplant (SCT) remains a standard of care in patients (pts) with newly diagnosed (ND) multiple myeloma (MM). While lenalidomide (R) maintenance is acknowledged to improve outcomes, intensified consolidation (such as tandem-SCT) has yielded conflicting results. Allogeneic (allo) SCT holds the promise of curative potential at the cost of higher treatment-related mortality (TRM). In a previous phase 2 study, we showed a very low TRM rate (6.1%) and feasibility of 12 months (mos) of R maintenance (maint), with auto/allo SCT after R/adriamycin/dexamethasone (RAD). This prompted us to compare, on a randomized rather than a “biological assignment” basis, a second auto- versus (vs) an allo-SCT in pts with an unfavorable prognosis. Methods: The current protocol (DSMM XIV, NCT01685814) was set up according to a double 2x2-factorial design. Post-induction (PInd) CR rate was the efficacy endpoint for the comparison of RAD vs bortezomib (V)/RD (VRD; 3 cycles each). If pts had achieved &gt;VGPR to HDT, a second randomization (2ndR) compared immediate R maint (arm A2) with a second auto-SCT (B2). In case of &lt; VGPR, pts were randomized between a second auto- (C2) and allo-SCT (D2). Planned R maint. duration was 36 mos, except after allo (12 mos). Results: Between 05/2012-06/2016, 476 pts were randomized and 469 received at least one dose of study drug. Pts’ median age was 55 (range, 32–65) years. 11.3% of pts had FISH del17p; 11.6% had t(4;14); and 4.4% had t(14;16). PInd CR rate was 11.8% (90% CI, 7.9%-16.3%) with RAD and 13.0% (90% CI, 8.9-18.0) with VRD (P = .697). 382 pts underwent R2 with 279 pts. (73%) in &gt;VGPR and 103 (27%) in &lt; VGPR, respectively. Median duration of R maint (N = 298) was 21.2 mos for A2, 23.1 mos for B2, 27.4 mos for C2, and 11.0 mos. for D2. At a median follow-up of 40.2 (0.5-87.0) months, median PFS from first randomization with RAD was 41.7 (95% CI, 35.4-48.5) mos vs. 53.7 (95% CI, 46.2-63.1) mos with VRD (P = .0439). Median PFS from 2ndR was 38.7 (95% CI, 30.3-47.3) mos for the 181 RAD vs. 50.7 (95% CI, 44.4-64.9) mos for the 201 VRD pts (P = .0126). Median overall survival (OS) cannot be estimated. With 47 deceased RAD vs 36 VRD pts, HR was .671 (95% CI, .435-1.037; P = .0703). Conclusions: In this study, median PFS benefit was 12 mos in favor of VRD vs. RAD despite comparable PInd CR. We show for the first time a len-PI to be superior to a len-chemo triplet, confirmed with positive OS trends. 3-year PFS for all consolidation arms will be presented. Clinical trial information: NCT01685814 .

Evaluating maintenance therapies in advanced oesophago-gastric adenocarcinoma (OGA): Interim analysis and biomarker results from the PLATFORM study.

282 Background: Advanced OGA patients (pts) are treated with platinum-based 1st line chemotherapy but the role of maintenance therapy once disease control is obtained is unknown. Methods: PLATFORM is a prospective, open-label, adaptive phase II trial assessing maintenance therapy in OGA. HER2 negative pts with advanced OGA achieving response or stable disease on completion of 1st line platinum-based chemotherapy were initially randomised to surveillance (A1), capecitabine (A2) and durvalumab (A3). Rucaparib (A4) and capecitabine+ramucirumab (A5) were subsequently added as part of adaptive design. Primary endpoint is progression-free survival with target recruitment of 154pts/arm. A pre-planned futility interim analysis (IA) is triggered when 61 pts/arm are recruited and evaluable using 12-week progression-free rate (PFR). Individual arms will continue accrual if the upper limit of 1-sided 95% CI difference is &gt; 0 when compared to A1. Biomarker analyses of A1 and A3 IA patients include: PDL1 as tumour and immune cell combined proportion (TIP), multiplex IHC of tumour infiltrating lymphocytes (TILs), TMB and MSI status by whole exome sequencing. Results: To date, 1053 pts have registered prior to or during 1st line therapy and 356 pts randomised. Primary attrition was due to disease progression. Baseline demographics in the IA population (arms A1 to A3, n = 183) were male (81%); median age 65 yrs; metastatic disease (92%); oesophageal (40%), OG junction (28%) and gastric (32%) primary. 12-week PFR were A1: 51% (95%CI: 38-64%); A2: 52% (95%CI: 40-65%); A3: 49% (95%CI: 36-62%). PFR differences to arm A1 were A2: 1.6% (95%CI: -13.2 to 16.5%); A3: -1.6% (95%CI: -16.5 to 13.3%). In A1, PFR was 53% vs 43% in PDL1 TIP &lt; 10% and ≥10% respectively. In A3, PFR was 51% vs 100% in PDL1 TIP &lt; 10% and ≥10% respectively. 3 pts in A3 had partial response; none were seen in A1 and A2. Density of TILs subsets, TMB and MSI data will be presented. Conclusions: PLATFORM IA did not indicate futility in maintenance capecitabine or durvalumab compared to surveillance in advanced OGA and will continue to target accrual. Incremental radiological responses were observed with maintenance durvalumab only. Clinical trial information: NCT02678182.

Secukinumab treatment in new‐onset psoriasis: aiming to understand the potential for disease modification – rationale and design of the randomized, multicenter STEPIn study

To date, biological treatments have been assessed in subjects with a long-term history of psoriasis and previous failures to systemic and topical therapies. In rheumatoid arthritis and other immune-mediated inflammatory diseases, early intensive systemic treatment prolongs treatment-free remission. We hypothesize that, by treating patients with psoriasis early with an effective systemic therapy, we may be able to alter the clinical outcome and the natural course of the disease. The STEPIn study (NCT03020199) investigates early intervention with secukinumab versus narrow-band ultraviolet B (nb-UVB) phototherapy in subjects with new-onset psoriasis. To determine whether early intervention with either nb-UVB treatment or secukinumab in subjects with new-onset plaque psoriasis might modify the natural course of the disease. One hundred and sixty subjects aged 18-50years with new-onset (≤12months) moderate-to-severe plaque psoriasis and naïve to systemic treatment and phototherapy will be randomized to secukinumab 300mg or nb-UVB. The Main Study has two treatment arms: Arm A1, subcutaneous secukinumab 300mg at baseline, Weeks 1, 2, 3 and 4, and every 4weeks thereafter until and including Week 52; Arm B1, one/two cycles of nb-UVB for 12weeks each (maximum 28-week break between cycles). After treatment discontinuation, patients will be followed up and monitored for disease activity up to Week 208. A Mechanistic Sub-study will assess immunological changes and pathogenic tissue-resident memory T cells in skin biopsies. STEPIn is the first study to investigate whether early intensive treatment in new-onset psoriasis can modify the long-term natural course of the disease and thus become a novel treatment strategy for patients with psoriasis.

Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)–An ACCRU Network study.

611 Background: Regorafenib is an oral multikinase inhibitor with survival benefit in refractory mCRC patients (pts). Toxicities such as Palmar-plantar erythrodysesthesia syndrome (PPES), fatigue and hypertension (HTN) have limited its use. Despite absence of supportive data, various dosing or interval scheduling have been implemented into clinical practice. Methods: A randomized phase II study of regorafenib dose-escalation (Arm A: 80 mg/day, weekly dose escalation if no significant drug-related toxicities, up to 160 mg/day) vs. standard dose (Arm B: 160 mg/day) in pts with mCRC for 21 days of a 28-day cycle. Pts were randomized 1:1:1:1 to arms A1 and B1 (Pre-emptive Clobetasol for PPES); A2 and B2 (Reactive Clobetasol). The primary endpoint was the proportion of patients who completed 2 cycles of treatment and initiated the 3rd in Arm A (Pooled A1 + A2) vs. Arm B (Pooled B1 + B2). Superiority for Arm A was to be declared if the one-sided p-value calculated using Fisher’s exact method was less than 0.2. Results: From June 2015 to June 2017, 123 pts were randomized with 116 (A = 54, B = 62) evaluable for the primary endpoint. Demographic data were well balanced with overall median age of 61yrs (range: 29-81), M/F (61/39%) and ECOG PS 0/1 (37/63%) and KRAS MT/WT/UNK (47/44/9%).The study met its primary endpoint with 43% of pts on Arm A initiating the 3rd vs. only 25% of pts Arm B [one-sided p-value 0.028]. Median Overall Survival (OS) was improved in Arm A vs. Arm B (9.0 mos vs. 5.9 mos; p = 0.094). Median Progression Free Survival (PFS) was 2.5 mos for Arm A vs. 2.0 mos for Arm B (p=0.553). Overall rates of grade 3/4 toxicity were more favorable for Arm A vs. Arm B (% PPES 15 vs. 16, HTN 7 vs. 15 and fatigue 13 vs. 18, respectively). Multiple QOL parameters were improved in A vs. B primarily at week 2 of the first cycle. Conclusion: A strategy with weekly dose escalation of regorafenib from 80 mg to 160 mg/day was found to be superior to a starting dose of 160 mg/day. These results establish a new standard for optimizing regorafenib dosing. Further data on outcomes of preemptive vs. reactive clobetasol strategies are undergoing analysis and will be presented later. Clinical trial information: NCT02368886.