First-line Treatment Of Pts Research Articles

LBA21 FOLFOX/FOLFIRI plus either bevacizumab or panitumumab in patients with initially unresectable colorectal liver metastases (CRLM) and left-sided and RAS/BRAFV600E wild-type tumour: Phase III CAIRO5 study of the Dutch Colorectal Cancer Group

Patients (pts) with initially unresectable CRLM may qualify for curative-intent local therapy after downsizing by induction systemic therapy. CAIRO5 was designed to find the optimal induction regimen. We present results of pts with left-sided and RAS/BRAFV600E wild-type tumour. Pts were randomised between FOLFOX/FOLFIRI (patient preference) plus either bevacizumab (arm A) or panitumumab (arm B) up to 12 cycles. Prior systemic or local therapy for metastases was not allowed. (Un)resectability of CRLM was assessed by a liver expert panel of surgeons and radiologists, at baseline by predefined criteria and every 2 months thereafter by individual opinion. Primary endpoint was progression-free survival (PFS). Pts were stratified by potentially resectable vs permanently unresectable CRLM, serum LDH (normal/abnormal) and choice of irinotecan vs oxaliplatin. 256 events were required to detect a hazard ratio (HR) of 0.70 for PFS with 80% power and 2-sided log-rank test at 5% assuming a median PFS of 11.6 months in arm A. 236 pts (118 in each arm) were included in 43 Dutch sites from November 2014 until closure due to futility in March 2022. 6 ineligible pts were excluded. Median follow up was 44 months. Main characteristics were (arm A/B): median age 59/60, male 61/63%, synchronous CRLM 88/92%, prior adjuvant chemotherapy 4/3%, median number of CRLM 12/12. With 197 events, median PFS in arm A vs B was 10.6 vs 10.3 months (stratified HR 1.12, 95% CI 0.84-1.50, p=0.44). Response rate (RR) was 52% vs 76% (p<0.01). Median depth of response (DOR) was 33% vs 49% (p<0.01). R0/1 resection ± ablation rate was 58% vs 56% (p=0.79). Grade ≥3 toxicity occurred in 52% vs 69% (p=0.01), Clavien Dindo grade ≥3 surgical complications in 21% vs 14% (p=0.30). In first-line treatment of pts with initially unresectable CRLM and left-sided and RAS/BRAFV600E wild-type tumour there is no difference in median PFS between the addition of either bevacizumab or panitumumab to FOLFOX/FOLFIRI. The addition of panitumumab significantly increases RR and DOR but this does not translate in an increased local therapy rate of CRLM.

S206: OBINUTUZUMAB PLUS CHEMOTHERAPY DEMONSTRATES LONG-TERM BENEFIT OVER RITUXIMAB PLUS CHEMOTHERAPY IN PATIENTS WITH PREVIOUSLY UNTREATED FOLLICULAR LYMPHOMA: FINAL ANALYSIS OF THE GALLIUM STUDY

Background: Immunochemotherapy with rituximab plus chemotherapy (R-chemo) has significantly improved outcomes for patients (pts) with previously untreated follicular lymphoma (FL). However, most pts still experience disease relapse, progression, or death. Obinutuzumab (G) is a type II anti-CD20 monoclonal antibody with enhanced direct cell killing, antibody-dependent cellular cytotoxicity and antibody-dependent phagocytosis versus R. The safety and efficacy of G-chemo versus R-chemo was assessed in pts with previously untreated, advanced stage FL in the randomized, Phase III GALLIUM (NCT01332968) study. In the primary analysis, G-chemo demonstrated a significant improvement in progression-free survival (PFS) versus R-chemo, with a manageable safety profile (Marcus, et al. 2017); this efficacy benefit was maintained after 5 years of observation (Townsend, et al. 2020). Aims: To report the final analysis of the GALLIUM study after a median observation time of 8 years. Methods: Pts aged ≥18 years with previously untreated histologic Grade 1–3a FL requiring treatment were enrolled. Pts were randomized 1:1 to receive G 1000mg intravenously (IV; Days [D]1, 8 and 15 of Cycle 1 and D1 of subsequent cycles) or R 375mg/m2 IV (D1 of each cycle) plus chemo for 6 or 8 cycles depending on the chemo backbone selected at each institution (cyclophosphamide, doxorubicin, vincristine, and prednisolone [CHOP]; cyclophosphamide, vincristine, and prednisolone [CVP]; or bendamustine). Pts attaining a complete or partial response received maintenance with the same antibody every 2 months for 2 years or until disease progression (PD). The primary endpoint was investigator-assessed PFS; secondary endpoints included time-to-next anti-lymphoma treatment (TTNLT), overall survival (OS) and incidence of adverse events (AEs). All pts provided written informed consent. Results: 1202 pts with FL were enrolled (G-chemo, n=601; R-chemo, n=601). As of July 30, 2021, median observation time was 8 years. Seven-year PFS was improved with G-chemo (63.4%) versus R-chemo (55.7%; hazard ratio [HR], 0.77; 95% confidence interval [CI]: 0.64–0.93; p=0.006; Figure). TTNLT was also improved with G-chemo versus R-chemo (HR, 0.71; 95% CI: 0.58–0.87; p=0.001); the proportion of pts who had not started their next treatment at 7 years was 74.1% and 65.4%, respectively. Disease transformation was observed in 4.2% of pts with G-chemo and 5.0% of pts with R-chemo. Seven-year OS was similar in both arms, 88.5% with G-chemo versus 87.2% with R-chemo (HR, 0.86; 95% CI: 0.63–1.18; p=0.36). Seventy-five pts in the G-chemo arm and 86 pts in the R-chemo arm had died, most commonly due to PD (4.2% and 6.0%, respectively). The incidence of serious AEs (SAEs) was 48.9% with G-chemo (28.2% and 24.4% during induction and maintenance, respectively) and 43.4% with R-chemo (24.6% and 21.7%, respectively). Rates of fatal AEs were similar with G-chemo (4.4%) and R-chemo (4.5%); pneumonia was the most common fatal AE (0.8% [n=5] and 0.2% [n=1], respectively) and SAE (5.9% [n=35] and 6.2% [n=37], respectively). Second malignancies occurred in 13.1% of pts in the G-chemo arm and 9.9% of pts in the R-chemo arm. After adjusting for observation time, rates were similar between arms. These safety findings are consistent with previous analyses. Image:Summary/Conclusion: After a median observation time of 8 years, a meaningful improvement in PFS was maintained with G-chemo versus R-chemo in pts with previously untreated FL, confirming the role of G-chemo as a standard of care for the first-line treatment of pts with FL.

Phase II study of nivolumab in combination with FOLFOXIRI/bevacizumab as first-line treatment in patients with advanced colorectal cancer RAS/BRAF mutated (mut): NIVACOR trial (GOIRC-03-2018).

3509 Background: FOLFOXIRI plus bevacizumab (BEV) represents standard chemotherapy in first-line treatment of patients (pts) with metastatic colorectal cancer (mCRC). The NIVACOR study evaluates the addition of nivolumab (NIV) to FOLFOXIRI/BEV as first-line therapy in mCRC RAS/BRAF mut pts regardless of MSS/MSI status. Methods: This is a single-arm, multicenter, open-label, phase II trial in first-line treatment of pts with mCRC RAS/BRAF mut. Pts received NIV at a flat dose of 240 mg q14 days, FOLFOXIRI (irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and 5-fluorouracil CI 3,200 mg/m2 for 48 hours) in combination with BEV at the dose of 5 mg/kg IV q14 days for eight cycles and then, the maintenance with BEV/NIV until PD or unacceptable toxicities. The primary endpoint was the ORR according to RECIST 1.1 Criteria. All images are reviewed by Independent Data Monitoring Committee. According to Fleming’s design with alpha and beta levels of 0.05 and 0.2 respectively, in a sample size of 73 pts (comprehensive of a 10% drop-out rate), at least 56 responses were necessary to not reject the alternative hypothesis of an ORR=0.80. Results: From October 2019 to March 2021, 73 pts were enrolled in 9 Italian centers. The median age was 60 (51-65) years and 50.7% were male; the main primary tumor side was right (50.7%). The molecular characterization was: 87.7% RAS mut, 16.2% BRAF mut, and 4.5% both RAS and BRAF mut; 10/62 were MSI (16.1%), 52/62 (83.9%) MSS, and 11 pts not assessed. Liver metastases were present in 56.2% pts. The median follow-up was 14.3 (IQR 11.5-16.5) months on December 31, 2021. The median (m) duration of treatment was 12 (8-17) cycles. The ORR was 76.7%, with 7(9.6%) CR and 49(67.1%) PR. SD were 15(20.6%) with a DCR of 97.3%; 2(2.7%) pts were not evaluable. The mDOR was 8.4 (95%CI, 7-NE) months. The mPFS was 10.1 months (95%CI, 9.4-NE) and 12-months PFS was 53.4%. At data cut-off, 65 (89.1%) pts are still alive. In subgroups analysis of MSS pts the ORR was 78.9% with a mDOR of 7.59 (95% CI 6.21 -11.43) months, DCR of 96.2%, and mPFS of 9.8 (95%CI 8.18-15.24) months. The surgery of the primary tumor, metastases, or both was performed in 6(8.2%), 9(9.6%), and 5(6.9%) of pts, respectively. The main grade (G) 3 -4 toxicities were: neutropenia (G3 21.9%, G4 15.1%), diarrhea (G3 17.8%, G4 1.4%), hypertension G3 (6.8%), fatigue G3 (6.8%), and febrile neutropenia G4 (4.1%). Conclusions: The primary endpoint ORR was met. These results show the preliminary efficacy and safety of NIV in combination with FOLOXIRI/BEV as first-line therapy in pts with mCRC RAS/BRAF mut. Also, promising activity was observed in MSS subgroup pts. These data support the conduction of phase III randomized-controlled study. Research Sponsor: Bayer, Bristol Myers-Squibb. Clinical trial information: NCT04072198.

A phase II clinical trial of camrelizumab (CAM, an IgG4 antibody against PD-1) combined with apatinib (APA, a VEGFR-2 tyrosine kinase inhibitor) and temozolomide (TMZ) as the first-line treatment for patients (pts) with advanced acral melanoma (AM).

9508 Background: PD-1 monotherapy as the first line stand treatment for advanced melanoma yields an objective response rate (ORR) of &lt; 20% in AM. Although multiple clinical trials are ongoing testing TMZ/APA, TMZ/PD-1 and APA/PD-1 combo therapies in AM, the reported ORR (range 17-23.8%) are far from satisfactory. We therefore conducted a phase II study of CAM/APA/TMZ combo in this subtype aiming for improved efficacy. Methods: We performed a single center, single arm phase II study (NCT04397770) testing the efficacy and safety of CAM/APA/TMZ combo as first-line therapy in pts with advanced AM. The primary endpoint was ORR per RECIST1.1, secondary endpoints included progression free survival (PFS), disease control rate (DCR), overall survival (OS), and safety. All pts received iv CAM (200mg q2w), iv TMZ (200mg/m2 d1-5, q4w) and po APA (250mg qd) until disease progression or intolerable toxicity. Results: By Jan 2022, fifty pts were enrolled (48 evaluable), the median follow-up was 12.1 mo (IQR 8.4-14.5). Thirty-one pts achieved CR/PR as the best response (including 1 CR and 30 PR), the ORR was 64.6% (95% CI 49.4-77.4%). The DCR was 95.8% (95%CI, 84.6-99.3%). Both the median PFS and OS was not reached (NR); 6-mo and 12-mo PFS rate was 81.7% (95%CI 71.6-93.3%) and 62.9% (95%CI 48.4-81.7%), respectively; 12-mo OS rate was 82.3% (95%CI 68.2-99.2%). The incidence of treatment-related adverse events (TRAEs) was 94% (47/50). Of 50 patients, the most common grade ≥3 TRAEs included γ-glutamyl transferase elevation (24.0%), direct bilirubin elevation (22.0%), aspartase transaminase elevation (20.0%), alanine transaminase elevation (16.0%), and hypertriglyceridemia (14.0%). No treatment-related deaths occurred. Conclusions: The CAM/APA/TMZ combination demonstrated promising efficacy as the first-line treatment for pts with advanced AM, and was generally well tolerated. Phase III randomized control trial is warranted. Clinical trial information: NCT04397770.

Phase 2 trial of enoblituzumab plus retifanlimab or tebotelimab in first-line treatment of patients (pts) with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

TPS6102 Background: Head and neck cancer accounts for ̃900,000 cases and over 400,000 annual deaths worldwide as of 2021. Pts with R/M SCCHN have a poor prognosis with median overall survival &lt;1 year. Programmed death (PD)-protein 1 (PD-1) and PD-ligand 1 (PD-L1) blockade has shown antitumor activity in advanced SCCHN. Enoblituzumab (MGA271) is an investigational monoclonal antibody (mAb) that binds B7-homolog 3 (B7-H3) with enhanced binding to the activating Fc gamma receptor CD16A, particularly the low-affinity allele CD16A-158. B7-H3 is overexpressed in many cancers, including SCCHN, but not in most normal tissues. Retifanlimab (MGA012, INCMGA00012) is an investigational anti-PD-1 mAb, blocking binding of PD-L1 or PD-ligand 2 (PD-L2) to PD-1. Tebotelimab (MGD013) is an investigational, Fc-bearing bispecific, tetravalent DART® molecule designed to bind PD-1 and lymphocyte activation gene 3, inhibiting their interaction with PD-L1 or PD-L2 and major histocompatibility complex class II. In vitro data suggest that both retifanlimab and tebotelimab have potential to sustain enoblituzumab-mediated immune activation and antitumor activity (Obara G, et al. Ann Oncol. 2021;32[suppl 5]:S814). Combination of enoblituzumab with retifanlimab or tebotelimab sustained the ability of natural killer cells and CD8+ T cells to produce interferon gamma upon restimulation. Both retifanlimab and tebotelimab enhanced enoblituzumab-dependent cytotoxicity targeting B7-H3–expressing tumor cells. In a phase 1/2 study, the combination of enoblituzumab with pembrolizumab was well tolerated (Aggarwal C, et al. J Immunother Cancer. 2022 [under review]). The overall response rate in anti-PD-1/PD-L1–naïve pts with SCCHN (post platinum) was 33% (6/18), including 1 confirmed complete and 5 confirmed partial responses, warranting further development of this combination in R/M SCCHN. Methods: This is an open-label, nonrandomized study in first-line treatment of pts with R/M SCCHN. Approximately 50 pts with PD-L1 combined positive score (CPS) ≥1 will receive enoblituzumab 15 mg/kg plus retifanlimab 375 mg and 30 pts with CPS &lt;1 will receive enoblituzumab 15 mg/kg plus tebotelimab 600 mg. Dosing is once every 3 weeks with tumor assessment at the end of Cycle 2 and every 3 cycles thereafter. Pts with no prior systemic therapy for R/M SCCHN are eligible. Pts who completed systemic therapy &gt;6 months before the study, if given as part of multimodal treatment for locally advanced disease, are eligible. In the tebotelimab cohort, safety data will be reviewed for dose-limiting toxicities through Cycle 2 Day 7 on the first 12 pts (2 mini cohorts of 6 pts each). All pts will be followed for survival after the last dose of study drug. The first pt was enrolled in March 2021, and 28 pts are on treatment as of January 19, 2022. Clinical trial information: NCT04634825.

Phase II study of nivolumab (nivo) with relatlimab (rela) in patients (pts) with first-line advanced melanoma: Early on-treatment major pathologic response on biopsy.

9514 Background: A phase II study of nivo and rela was designed to evaluate the antitumor activity and mechanism of this combination and components for first-line treatment of pts with advanced melanoma. Pts received lead-in treatment with 1 cycle of nivo (480mg IV q4wk), rela (160mg IV q4wk), or nivo-rela followed by combination therapy. We assessed the effect of each lead-in treatment on immune-related pathological response (irPR) at 4-wk biopsy to develop early biomarkers of antitumor response. Methods: Core biopsy of an index lesion was performed at baseline and after 4 wk on-treatment. Immune characteristics of pathological response were assessed on H&amp;E sections, including presence of tumor-infiltrating lymphocytes (TIL), neovascularization, proliferative fibrosis, plasma cells, and lymphoid aggregates. irPR score was calculated as described by Stein JE et al Ann Oncol 2019, from 0 (no irPR features) to 3 (major pathologic response on biopsy [MPRbx], ≤10% residual viable tumor). We assessed the association between irPR and radiological response (RECIST v1.1) at 4-wk evaluations. Results: The current cohort includes 22 pts, median age = 67, male = 13. Pts were randomized to nivo = 7, rela = 7, and nivo-rela = 8 lead-in groups. Two pts had no irPR evaluation due to early progression and unscorable tumor. Among 20 evaluable pts, proliferative fibrosis, neovascularization, plasma cells, brisk TIL, and lymphoid aggregates were identified in 50%, 35%, 26.3%, 25%, and 5% of cases, respectively. Lead-in nivo (n = 2/6), rela (n = 0/6), and nivo-rela (n = 3/8) resulted in irPR = 3 in 25% of pts. Radiological response was identified as partial response (PR) = 1/22 (4.5%), stable disease (SD) = 12/22 (54.5%), and progressive disease (PD) = 9/22 (41%). Among pts with PD, 44% received rela-, 33% nivo-, and 22% nivo-rela- lead-in. Pts with irPR score = 3 had radiological PR = 1, SD = 3, and PD = 1 at 4wks. No association was found between MPRbx and radiological response at 4 wks. Conclusions: Four-wk MPRbx may serve as an early biomarker of treatment response in advanced melanoma. Lead-in treatment resulted in MPRbx of 25% and was greatest with nivo-rela lead-in. Correlations between 4 wk MPRbx and later radiological responses, survival and other endpoints will be made at completion of trial accrual. Clinical trial information: NCT03743766. [Table: see text]

Final overall survival analysis and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER: Nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma.

350 Background: First-line nivolumab plus cabozantinib (N+C) demonstrated superiority over sunitinib (SUN) in the primary disclosure of the phase 3 CheckMate 9ER trial (NCT03141177; 10.6 months minimum follow-up; Choueiri TK et al. N Engl J Med 2021) in patients (pts) with advanced renal cell carcinoma (aRCC). Here, we report the preplanned final overall survival (OS) analysis with updated efficacy and safety in intent-to-treat (ITT) pts, and an exploratory assessment of target lesions by organ site after extended follow-up. Methods: Pts with aRCC (clear cell component) were randomized to N 240 mg every 2 weeks + C 40 mg once daily vs SUN 50 mg once daily (4 weeks of 6-week cycles). The primary endpoint was RECIST v1.1–defined progression-free survival (PFS) by blinded independent central review (BICR) in ITT pts; secondary endpoints included OS, objective response rate (ORR) by BICR, and safety. The preplanned final OS analysis was set to occur after observing 254 events. Maximal reduction of target lung, lymph node, kidney, and liver lesions were evaluated per BICR via post hoc exploratory analyses. Results: After 25.4 months minimum follow-up (median, 32.9 months) for OS in ITT pts, a total of 271 OS events occurred, and N+C continued to demonstrate OS improvement vs SUN (N = 323 vs 328; median 37.7 vs 34.3 months; HR 0.70 [95% CI 0.55–0.90]). PFS (median 16.6 vs 8.3 months; HR 0.56 [95% CI 0.46–0.68]) and ORR (55.7% [95% CI 50.1–61.2] vs 28.4% [95% CI 23.5–33.6]) benefits were maintained with N+C vs SUN, and 12.4% (N+C) vs 5.2% (SUN) of pts had a complete response. Median duration of response was 23.1 months with N+C vs 15.1 months with SUN. A higher percentage of pts experienced any reduction and ≥30% reduction from baseline with N+C vs SUN in target lesions at all organ sites assessed (Table). Among all treated pts, 97.2% (N+C; N = 320) vs 93.1% (SUN; N = 320) had a treatment-related adverse event (TRAE) of any grade (65.0% vs 54.1% had a grade ≥ 3 TRAE). Conclusions: N+C continued to provide survival improvement vs SUN among ITT pts in the final OS analysis, additionally PFS and ORR benefits with N+C were sustained with minimum 2-year follow-up. A higher proportion of pts experienced tumor shrinkage benefit with N+C vs SUN across all 4 organ sites assessed. No new safety signals emerged with extended follow-up in either arm. These results highlight N+C as a first-line treatment for pts with aRCC. Clinical trial information: NCT03141177. [Table: see text]

Abstract P1-18-03: Alpelisib + fulvestrant in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + aromatase inhibitor (AI): 18-month follow-up of BYLieve Cohort A

Abstract Introduction: In HR+, HER2- ABC, activating PIK3CA mutations occur in ~40% of tumors and confer worse prognosis, including endocrine therapy (ET) resistance. BYLieve (NCT03056755) is an ongoing Phase II, open-label, 3-cohort noncomparative study, evaluating the PI3Kα inhibitor and degrader alpelisib (ALP) + ET (fulvestrant [FUL] or letrozole) in patients (pts) with PIK3CA-mutated, HR+, HER2- ABC progressing on/after prior treatment, including CDK4/6i + ET. This study is of high clinical relevance as ET + CDK4/6i is the recommended standard of care for first-line treatment of pts with HR+, HER2- ABC. In Cohort A, pts received CDK4/6i + AI as immediate prior therapy and received ALP + FUL as study treatment. In the primary analysis, the primary endpoint was met with 50.4% (95% confidence interval [CI], 41.2%-59.6%) of the 121 pts in the Cohort A modified full analysis set (mFAS) alive and without disease progression at 6 mo. Median progression-free survival (mPFS) and overall survival (mOS) were 7.3 mo (95% CI, 5.6-8.3) and 17.3 mo (95% CI, 17.2-20.7), respectively. The most frequent grade ≥3 adverse events (AEs) in the 127 pts in the Cohort A safety set were hyperglycemia (28%), rash (9%), and rash maculopapular (9%). This analysis focuses on updated efficacy and safety endpoints reflective of all pts achieving ~18-mo follow-up. Methods: Pts in Cohort A received ≥1 dose of ALP 300 mg orally QD + FUL 500 mg intramuscular Q28D + C1D15. For the 18-mo follow-up, efficacy endpoints, including PFS, OS, overall response rate (ORR), clinical benefit rate (CBR), duration of response (DOR) in pts with complete or partial response, and PFS on next line of treatment (PFS2), will be analyzed on the mFAS, which includes pts with a centrally confirmed PIK3CA mutation in tumor tissue. Safety of ALP + FUL, including AEs and laboratory toxicities, will be evaluated in the safety set, which includes all pts who received ≥1 dose of study treatment. Results: Of the 127 pts enrolled in Cohort A and part of the safety set, 121 were included in the mFAS. We will present efficacy endpoint results from the pts in Cohort A along with the long-term safety profile of the ALP + FUL combination. Conclusion: These data will provide insights on the long-term efficacy and safety of ALP + FUL. This combination is currently approved and used, in the clinical setting, for the treatment of pts with HR+, HER2- PIK3CA-mutated ABC. Citation Format: Eva M Ciruelos, Florence Lerebours, Hope S Rugo, Manuel Ruiz-Borrego, Pamela Drullinsky, Aleix Prat, Thomas Bachelot, Patrick Neven, Yeon Hee Park, Nicholas Turner, Dejan Juric, Ennan Gu, Christina H Arce, Murat Akdere, Stephen Chia. Alpelisib + fulvestrant in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), PIK3CA-mutated advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) + aromatase inhibitor (AI): 18-month follow-up of BYLieve Cohort A [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-03.

117TiP A phase II study of toripalimab combined with paclitaxel/carboplatin for the first-line treatment of advanced thymic carcinoma

117TiP A phase II study of toripalimab combined with paclitaxel/carboplatin for the first-line treatment of advanced thymic carcinoma

1207O Bevacizumab + erlotinib vs erlotinib alone as first-line treatment of pts with EGFR mutated advanced non squamous NSCLC: Final analysis of the multicenter, randomized, phase III BEVERLY trial

Adding bevacizumab to erlotinib prolonged PFS in NEJ026 and CTONG 1509 trials, but limited data are available in non-Asian patients (pts). BEVERLY is an Italian no-profit, randomized, open-label, multicenter phase III trial of bevacizumab (BEV) plus erlotinib (E) vs E alone as first-line treatment for EGFR-mutated advanced NSCLC. Eligible pts were randomized 1:1 to E (150mg daily) alone or combined with BEV (15mg/kg iv q3w) until disease progression or unacceptable toxicity. Center, ECOG PS and type of mutation (ex19 deletion vs ex21 L858R vs others) were stratification variables. Co-primary endpoints were investigator-assessed PFS (IA-PFS) and blinded-independent centrally-reviewed PFS (BICR-PFS). Secondary endpoints were OS, QoL, IA- and BICR- objective response rate (ORR) and safety; biomarker analyses are also planned. 126 events out of 160 randomized pts were required to detect a PFS prolongation with BEV from 10 to 16.7 mos (HR 0.60), with 2-sided α=0.05, 80% power. From Apr 11, 2016 to Feb 27, 2019, 160 pts were randomized to BEV+E (80) or E alone (80). Pts were mainly female (63.8%), never smokers (51.9%), ECOG PS 0-1 (98.1%), median age 66 (IQR 59-73); 55% of pts had ex19Del and 41% L858R mutation. At a median follow-up of 31 mos, 130/160 (81.3%) pts had a PFS event (progression or death) and 84/160 (52.5%) died. BEV+E significantly prolonged IA-PFS over E alone with a median of 15.4 vs 9.7 mos (HR 0.60; 95%CI 0.42-0.85, log-rank P=0.0039). Median OS was 28.4 vs 23.0 mos in BEV+E and E arms, respectively (HR 0.70; 95%CI 0.46-1.10, log-rank P=0.12). One toxic death was reported, due to intracranial hemorrhage with BEV+E. Hypertension (any grade: 49% vs 18%; grade≥3: 24% vs 5%), skin rash (grade≥3: 31% vs 14%), thromboembolic events (any grade: 11% vs 4%), and proteinuria (any grade: 23% vs 6%) were more frequent with the experimental combination treatment. The addition of BEV to E significantly prolonged IA-PFS compared with E alone as first-line treatment in Italian EGFR-mutated NSCLC patients, with no unexpected safety issues. Blinded radiologic revision of PFS and ORR is ongoing and will be presented at the meeting.

Safety, tolerability and preliminary efficacy of CAN04, a first in class monoclonal antibody against IL1RAP, in combination with nab-paclitaxel and gemcitabine (NG) in subjects with pancreatic cancer.

e16228 Background: Interleukin-1 Receptor Accessory Protein (IL1RAP) is expressed on cancer and stromal cells in many solid tumors. CAN04 is a fully humanized IgG1 targeting IL1RAP blocking IL-1α and β signaling and triggering ADCC. As monotherapy, CAN04 has been administered without reaching MTD up to 15mg/kg. We report initial data from CAN04 in combination with NG in pts with pancreatic cancer (PDAC). Methods: Primary objective was to determine safety and tolerability of CAN04 in combination with standard NG as first line treatment in pts with locally advanced/metastatic PDAC. Secondary objectives included establishing preliminary efficacy. Tumor responses were evaluated according to RECIST/iRECIST. Results: 36 patients (pts) received at least 1 dose of CAN04: median age 62 yrs (46-87), 47% women, 94% stage IV, 8% had received prior adjuvant therapy; 59% ECOG 0, 41% ECOG 1. Dosing was initiated at 5mg/kg, escalated to 7.5mg/kg (n = 8) which was considered above MTD due to hematological toxicity, followed by expansion at 5mg/kg. Infusion related reactions (IRRs) were seen primarily with CAN04 priming dose of 0.5 mg/kg (25% G1, 25% G2, 3% G3). G3 or higher AEs (all/related) were dominated by hematological toxicity and reported in 89%/72% of pts (see table). SAEs were reported in 67% pts (44% G3/G4), in 33% considered related (19% G3/G4). 33% of pts discontinued due to AEs: 4 deterioration of general condition, 2 IRR, 2 bilirubin elevation, 1 bile duct obstruction, 1 hemolytic uremic syndrome, 1 pancreatitis, 1 asthenia, 1 decreased appetite, 1 pneumonitis. There were 3 on treatment deaths: disease progression, gastrointestinal obstruction and cholangitis. For the mITT efficacy analysis (n = 31), 5 pts were excluded: 3 discontinued before receiving NG (2 consent withdrawals after IRRs, tumor related physical deterioration) and 2 did not complete Cycle 1 due to cholangitis and GI obstruction respectively. 12 pts (39%) had confirmed or unconfirmed PR as best response, 8 (26%) more showed SD and 9 (29%) had PD. Six pts underwent PD confirmation: 3 pts had prolonged immune unconfirmed PD (iUPD) by iRECIST and &gt; 50% decreases in CA19-9 and were on treatment for 4.5 (ongoing), 6 and 8 months, respectively. Clinical benefit rate (PR+SD+prolonged iUPD): 74%. At the time of this analysis, 12 pts (38%) are ongoing. Median duration of response is currently 7.5 months (1.8-13.8 months). Conclusions: The clinical benefit rate of CAN04 in combination with NG is encouraging (74%). The G3/G4 neutropenia and febrile neutropenia rate is higher than expected for NG alone. Expansion cohorts at lower CAN04 doses have been initiated. Clinical trial information: NCT03267316. [Table: see text]

Health-related quality-of-life (HRQoL) analysis from the phase 3 CLEAR trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) for patients (pts) with advanced renal cell carcinoma (aRCC).

4502 Background: LEN + PEMBRO improved PFS, OS and ORR vs SUN in the first-line treatment of pts with aRCC; LEN + EVE improved PFS and ORR vs SUN (Motzer R et al. NEJM. 2021). We report results of a secondary objective of the CLEAR trial comparing the impact of LEN + PEMBRO or EVE vs SUN, on HRQoL. Methods: Pts (N=1069) were randomized (1:1:1) to receive LEN 20 mg PO QD + PEMBRO 200 mg IV Q3W; LEN 18 mg + EVE 5 mg PO QD; or SUN 50 mg PO QD (4 wks on/2 wks off). HRQoL was assessed per FKSI-DRS, EORTC QLQ-C30, and EuroQoL EQ-5D-3L, at baseline, on day 1 of subsequent 3 wk cycles starting with cycle 2, and at the off-treatment visit. HRQoL analyses (unless otherwise noted) were based on data from randomized pts with any HRQoL data who received ≥1 dose of study treatment. No adjustments for multiple testing or estimation were used; P-values and CIs are nominal and descriptive. Results: For comparisons of LEN + PEMBRO vs SUN, overall changes from baseline at mean follow-up (wk 46) favored LEN + PEMBRO with significant differences between treatments for physical functioning (least squares mean difference [LS MD] [95% CI]: 3.0 [0.5, 5.5]) and fatigue (−2.8 [−5.5, −0.1]), dyspnea (−2.8 [−5.3, −0.3]), and constipation (−2.2 [−4.2, −0.2]). LS MD of the FKSI-DRS total score was 0.2 (−0.4, 0.7). For comparisons of LEN + EVE vs SUN, overall changes from baseline at wk 46 favored SUN with significant differences in overall HRQoL (−2.8 [−5.1, −0.5] assessed by the EORTC QLQ-C30 GHS/QoL scale) and pain (2.8 [0.1, 5.5]), appetite loss (4.2 [1.3, 7.1]), and diarrhea (5.3 [2.6, 7.9]). LS MD of the FKSI-DRS total score was −0.4 (−1.0, 0.2). 14 of 18 scales for both LEN + PEMBRO and LEN + EVE vs SUN had no significant differences in LS MD comparisons. The LEN + PEMBRO arm is favored over SUN for the median time to first deterioration (TTD) for physical functioning, dyspnea, appetite loss and EQ-5D VAS (Table). 15 of 19 scales for both LEN + PEMBRO and LEN + EVE vs SUN had no significant differences in TTD comparisons. Conclusions: Compared with SUN, pts in LEN + PEMBRO group had similar or better symptoms and HRQoL. Clinical trial information: NCT02811861. [Table: see text]

Survival benefit of nephrectomy prior to immunotherapy-based combinations in patients with metastatic renal cell carcinoma: An FDA pooled analysis.

4516 Background: Immunotherapy-based combination therapies (IO-X) are standard of care for metastatic RCC (mRCC) in the frontline setting. Limited data is available on the role of cytoreductive nephrectomy prior to IO-X in patients (pts) with mRCC (Bakouny, et al. GU ASCO 2020). We assessed the correlation between nephrectomy prior to IO-X and overall survival (OS) in pts with de novo mRCC. Methods: We pooled data from trials submitted for FDA review of a checkpoint inhibitor combination as first-line treatment for pts with mRCC. We only included trials with available data for stage at initial diagnosis (dx) to identify pts with stage IV disease at initial dx and to exclude those with nephrectomy in the non-metastatic setting. Kaplan-Meier method was used to estimate median OS in pts with de novo mRCC with and without nephrectomy prior to IO-X. Results: Five trials met inclusion criteria, all of which evaluated IO in combination with a kinase inhibitor. Data for stage at initial dx was available in 1708 pts who received IO-X. The majority of pts were male (72%) and White (80%). Among the 849 pts (50%) with stage IV RCC at initial dx, 523 pts (62%) had nephrectomy prior to IO-X. All pts had clear cell histology; Sarcomatoid differentiation was present in tumor pathology of 25% and 10% of pts with and without prior nephrectomy, respectively. Proportion of pts with favorable, intermediate and poor risk disease was 10%, 70% and 20%, respectively. OS appeared better in those with stage IV disease at dx who had prior nephrectomy compared to pts without nephrectomy (Hazard ratio (HR) = 0.53, 95% CI: 0.42, 0.68), even after adjusting for age and prognostic risk group (HR = 0.59, 95% CI: 0.46, 0.75) (see table). Conclusions: In this retrospective exploratory analysis, nephrectomy prior to IO-X in pts with new dx of stage IV RCC appeared to be associated with improved OS, even when controlling for age and prognostic risk group. The decision for nephrectomy is affected by factors such as medical comorbidities which could not be completely controlled. Results should be considered hypothesis generating.[Table: see text]

Lenvatinib (LEN) + pembrolizumab (PEMBRO) treatment in patients (pts) with metastatic clear cell renal cell carcinoma (RCC): Final results of a phase 1b/2 trial.

e16542 Background: Immune checkpoint inhibitors (ICIs) are commonly used as first-line treatment for pts with advanced RCC. In the recent phase 3 CLEAR trial, LEN + PEMBRO showed improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) vs sunitinib in first-line treatment of advanced RCC (Motzer R et al. NEJM. 2021). Additional treatment options are needed for pts with disease progression on ICIs. A phase 1b trial of LEN + PEMBRO was performed in multiple tumor types and included an expansion part into a phase 2 cohort of ICI-pretreated, treatment-naïve, or previously treated ICI-naïve pts with metastatic RCC (NCT02501096). We report the final results of the RCC cohort with an extended follow-up. Methods: Eligible pts were ≥18 years old and had measurable disease. Efficacy analyses were conducted by prior therapy grouping. The primary endpoint was ORR at week 24 (ORRwk24) per immune-related (ir) RECIST by investigator assessment. Secondary endpoints included ORR, duration of response (DOR), PFS, OS, and safety. Exploratory endpoints included tumor response assessed per RECIST v1.1 by independent review committee (IRC). Subgroup analyses of the ICI-pretreated group will be included in the poster. Results: The recommended doses determined in phase 1b were LEN 20 mg daily + PEMBRO 200 mg once every 3 weeks (Taylor M et al. JCO. 2020). The study enrolled 145 pts (efficacy analysis, n=143; safety analysis, n=145). At data cutoff (August 18, 2020), the median follow-up time was 19.8 months. The ORRwk24 was 55.8% (95% CI 45.7–65.5) for ICI-pretreated pts (n=104), 72.7% (95% CI 49.8–89.3) for treatment-naïve pts (n=22), and 41.2% (95% CI 18.4–67.1) for previously treated ICI-naïve pts (n=17). The median OS for the previously treated ICI-naïve pts was 30.3 months and was not reached in the other groups. Additional efficacy analyses are shown in the table. Treatment-related adverse events occurred in 99.3% of pts; the most common were fatigue (58.6%), diarrhea (55.2%), and hypertension (40.0%). Most pts (69%) maintained the LEN starting dose or were reduced to LEN 14 mg daily (dose level −1). Conclusions: LEN + PEMBRO demonstrated promising antitumor activity with a manageable safety profile in pts with metastatic RCC, including pts who were ICI-pretreated. Clinical trial information: NCT02501096. [Table: see text]

Abstract PD3-02: Final analysis of PERTAIN: A randomized, two-arm, open-label, multicenter phase II trial assessing the efficacy and safety of first-line pertuzumab given in combination with trastuzumab plus an aromatase inhibitor in patients with HER2-positive and hormone receptor-positive metastatic or locally advanced breast cancer

Abstract Background The role of bidirectional cross talk between the HER2 and estrogen receptors in resistance to anti-HER2 and endocrine therapy has been studied extensively (Kaufman et al. J Clin Oncol 2009; Arpino et al. J Natl Cancer Inst 2007). The CLEOPATRA study showed that first-line pertuzumab (P) + trastuzumab (H) + docetaxel (T) improved progression-free survival (PFS) and overall survival (OS) significantly compared with placebo + H + T in patients (pts) with HER2-positive metastatic BC (MBC) (Baselga et al. N Engl J Med 2012; Swain et al. Lancet Oncol 2013; N Engl J Med 2015; N Engl J Med 2020). PERTAIN (NCT01491737) was the first randomized phase II trial to assess the addition of P to H + an aromatase inhibitor (AI) ± induction chemotherapy for the first-line treatment of pts with HER2-positive and hormone receptor-positive MBC or locally advanced BC (LABC). PERTAIN met its primary PFS endpoint at 31 months’ median follow-up, with a potentially enhanced effect in some groups, such as pts who did not receive induction chemotherapy (Rimawi et al. J Clin Oncol 2018). We present the final analysis at more than 6 years’ median follow-up, including updated PFS, mature OS (secondary endpoint), and updated safety. Methods Pts were randomized 1:1 to P + H + AI (Arm A) or H + AI (Arm B). P was given as an 840 mg intravenous (IV) loading dose followed by 420 mg every 3 weeks (q3w); H IV, at 8 mg/kg followed by 6 mg/kg q3w; anastrozole, at 1 mg daily; or letrozole, at 2.5 mg daily. Induction IV chemotherapy with T q3w or weekly paclitaxel could be given for 18-24 weeks at the investigator’s discretion before the start of endocrine therapy. Treatment was given until disease progression or unacceptable toxicity. Pts were stratified by induction chemotherapy (yes/no) and time since adjuvant hormone therapy (&amp;lt;12 months, ≥12 months, no adjuvant hormone therapy). Time-to-event endpoints were analyzed using Kaplan-Meier methods. Results Pts were randomized across 71 sites and 8 countries between Feb 2012 and Oct 2014. Intent-to-treat populations were 129 pts per arm; safety populations, 127 and 124 in Arms A and B, respectively; induction chemotherapy was received by 75 and 71 pts, respectively. Baseline demographics and disease characteristics were generally balanced between arms. Efficacy results are shown in the table. One hundred twenty-two pts per arm reported adverse events (AEs) at any grade (96.1% in Arm A; 98.4% in Arm B); 72 (56.7%) and 51 pts (41.1%) had grade ≥3 AEs, the most common grade ≥3 AEs (≥5.0%; Arm A vs. Arm B) being hypertension (11.8% vs. 10.5%), diarrhea (9.4% vs. 2.4%), and neutropenia (3.1% vs. 7.3%). Conclusions With a median follow-up of more than 6 years at final analysis, the PFS benefit of adding P to H + an AI was maintained. OS was similar between arms. A potentially enhanced treatment effect was observed by addition of P to H + an AI in pts who did not receive induction chemotherapy after randomization. There were no new safety concerns at final analysis. Overall, PERTAIN provides additional evidence on the role of P + H in the first-line treatment of HER2-positive MBC/LABC and suggests that some pts benefit from P + H + AI without induction chemotherapy. Arm AArm BMedian PFS, mo HR (95% CI)ITT21160.7 (0.5-0.9) p=0.006With induction17170.7 (0.5-1.0) p=0.08No induction27120.7 (0.4-1.0) p=0.07Median OS, mo HR (95% CI)ITT60571.1 (0.7-1.5) p=0.8With induction59661.2 (0.7-1.9) p=0.5No induction65540.9 (0.5-1.6) p=0.7CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; mo, months. Citation Format: Grazia Arpino, Juan de la Haba-Rodriguez, Jean-Marc Ferrero, Sabino De Placido, Dirk Klingbiel, Valentine Revelant, Christine Wohlfarth, Raf Poppe, Mothaffar F Rimawi. Final analysis of PERTAIN: A randomized, two-arm, open-label, multicenter phase II trial assessing the efficacy and safety of first-line pertuzumab given in combination with trastuzumab plus an aromatase inhibitor in patients with HER2-positive and hormone receptor-positive metastatic or locally advanced breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD3-02.

CYCLONE 2: A phase II, randomized, placebo-controlled study of abiraterone acetate plus prednisone with or without abemaciclib in patients with metastatic castration-resistant prostate cancer.

TPS5591 Background: Despite recent advances, nearly all patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) experience disease progression and cancer-specific mortality. Persistent or reactivated androgen receptor (AR) signaling and/or activation of pathways in cross-talk with AR signaling are key drivers of mCRPC progression. Evidence suggests that AR signaling promotes translation of D-type cyclins resulting in cyclin-dependent kinase 4 and 6 (CDK4&amp;6) activation and cell cycle progression. Abemaciclib is an oral selective inhibitor of CDK4&amp;6 dosed on a continuous schedule, that is FDA-approved in combination with endocrine therapy or as monotherapy to treat HR+, HER2- metastatic breast cancer pts. Preclinical studies with prostate cancer cell lines and xenograft models showed that abemaciclib induces cell cycle arrest and tumor growth inhibition. The hypothesis is that addition of abemaciclib to AR targeted therapy may be an effective treatment for mCRPC pts. Methods: CYCLONE 2 (NCT03706365) is a phase II, randomized, double-blind, multicenter, placebo-controlled study to assess the safety and efficacy of abemaciclib in combination with abiraterone acetate plus prednisone (AA+P) as first-line treatment of pts with mCRPC. The study is designed in two parts. Part 1 is a 30-patient safety lead-in to determine the recommended phase II dose (RP2D; 150 mg or 200 mg, twice daily) of abemaciclib in combination with AA (1000 mg, once daily) + P (5 mg, twice daily). In part 2, 150 pts are randomized 1:1 to abemaciclib at the RP2D with AA+P or placebo with AA+P. Pts who received prior AA+P, enzalutamide, apalutamide, darolutamide, radiopharmaceuticals, or sipuleucel-T are excluded. Prior docetaxel for metastatic hormone-sensitive prostate cancer, but not for mCRPC, is allowed. Pts must have progressive mCRPC (by PSA and/or imaging) and an accessible metastatic lesion for tumor biopsy. The co-primary objectives are radiographic PFS (per RECIST1.1 for soft tissue and PCWG3 for bone) and time to PSA progression. Secondary objectives include safety, objective response rate, duration of response, OS, time to symptomatic progression, and pharmacokinetics. Assuming hazard ratios of 0.64 (rPFS) and 0.6 (PSA progression), the study is powered to 80% and 85%, respectively, to test the superiority of abemaciclib plus AA+P vs. placebo plus AA+P at one-sided α=0.1 using stratified log-rank tests. Part 1 is completed and part 2 is enrolling in 70 sites worldwide. Clinical trial information: NCT03706365 .

Abstract PD1-03: A multicenter phase II study evaluating the efficacy of nivolumab plus paclitaxel plus bevacizumab triple-combination therapy as a first-line treatment in patients with HER2-negative metastatic breast cancer: WJOG9917B NEWBEAT trial

Abstract Background: PD-1 inhibitors have been developed for various cancer types, including breast cancer. Potential synergistic effects of nivolumab, paclitaxel and bevacizumab in combination was reported in preclinical models. Therefore, we initiated this investigator-initiated trial to evaluate the efficacy and safety of nivolumab + paclitaxel + bevacizumab therapy for metastatic breast cancer (MBC) patients (pts).Methods: This is a Phase II, multi-center, single-arm study to evaluate the efficacy and safety of nivolumab + paclitaxel + bevacizumab combination therapy as a first-line treatment for pts with HER2— MBC. Patients received nivolumab 240 mg/body on day 1, 15, paclitaxel 90 mg/m2 on day1, 8, 15, and bevacizumab 10 mg/kg on day1, 15 every 4 weeks until disease progression or intolerable toxicity experienced. The primary endpoint is the objective response rate (ORR) by independent central assessment. Key secondary endpoints include disease control rate (DCR: CR+PR+SD), progression free survival (PFS), overall survival, and the toxicity. The threshold and expected ORR are 55% and 70%, respectively, and 47 patients are needed to ensure a statistical power of 80% (α=0.10). Results: From February 2018 to October 2018, 57 female HER2— MBC pts were enrolled. Thirty-nine pts (68%) were with hormone receptor-positive (HR+), and 18 pts (32%) were with triple negative breast cancer (TNBC). ORR based on investigator assessment was 75.4%, and DCR was 96.4%. ORR was 71.7% (28/39) in pts with HR+ breast cancer and 83.3% (15/18) in pts with TNBC. Median PFS was not reached with median follow-up time of 10.7 months, and PFS rate at 12 months was 75.8% (95%CI: 60.9-86.2). Median OS was not reached and OS rate at 12 months was 87.1% (95%CI: 70.7-94.9). Thirty-five pts (59%) were still under treatment at the data cut-off date (1st June 2019). All pts had ≥1 AE; 58% of pts had Grade 3 or 4 AEs and 17% of pts had Grade 3 or 4 immune related-AEs. Twenty two percent of pts had serious AEs (SAE), and 12% of pts had nivolumab-related SAEs. Among the pts with nivolumab-related SAEs, 71% of them had recovered from SAEs. No treatment-related death was observed. Primary endpoint of ORR by independent central assessment and subset analysis with PD-L1 expression on tumor tissue (CPS, TPS by 28-8 antibody and IC, TC by SP142 antibody) will be presented at the symposium. Conclusions: This is the first study showing the promising efficacy of Nivolumab in combination with paclitaxel plus bevacizumab as a first line treatment for HER2— MBC. This triple-combination strategy for breast cancer warrants further study. Clinical trial information: UMIN000030242.Funding: This trial is sponsored by Ono pharmaceutical company. ResponseTotal100% (N = 57)Partial response (PR)75.4% (N = 43)Stable disease (SD)21.1% (N = 12)Progressive disease (PD)1.7% (N = 1)Objective response rate (ORR)75.4% (N = 43)Disease control rate (DCR) :CR+PR+SD96.4% (N = 55) Citation Format: Yukinori Ozaki, Toru Mukohara, Junji Tsurutani, Masato Takahashi, Koji Matsumoto, Manabu Futamura, Norikazu Masuda, Shigehisa Kitano, Kenichi Yoshimura, Hironobu Minami, Toshimi Takano. A multicenter phase II study evaluating the efficacy of nivolumab plus paclitaxel plus bevacizumab triple-combination therapy as a first-line treatment in patients with HER2-negative metastatic breast cancer: WJOG9917B NEWBEAT trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD1-03.

T-Cell Mediated Cytopenias in Patients with Myelodysplastic Syndromes Respond to Intravenous Immunoglobulin

Background: Patients with Myelodysplastic Syndrome (MDS) with cytopenias have limited treatment options to improve blood counts apart from immune-modulatory drugs (IMIDS), hypomethylating agents (HMA), cytokines and transfusional support. Immune dysregulation is common in MDS and occurs in up to 35% of pts (LR Silverman, Cancer Med, 2017). Expanded T-cell clonal populations in the peripheral blood and bone marrow in the presence of MDS may play a role in aggravating MDS related cytopenias, increasing the need for transfusions or exacerbating symptoms. Intravenous immunoglobulin (IVIG) may interact with Fc receptors on T cells or have suppressive effects on the concurrent large granular lymphocytic leukemia (LGL) clone. Targeted therapy with IVIG could be a novel strategy to mitigate the cytopenias in MDS and other bone marrow failure pts. Methods: We reviewed in a single-center series 27 consecutive pts who had either MDS, aplastic anemia (AA), or a myeloproliferative neoplasm (MPN) along with an LGL clone seen on TCR-rearrangement studies and/or peripheral blood flow cytometry in the blood and/or bone marrow. Of the 27 pts, 22 had MDS, 2 had MPN, and 1 each with AA, LGL, or Multiple Myeloma. IVIG was initially used as a single agent administered at a dose of 500mg/kg/day over 4 hours once weekly x4 weeks. After "induction", administration was changed to every other week, and then in responding pts, the interval was extended to every 3-4 weeks. In pts with a stable response, IVIG was discontinued and pts observed. After the initial 4 pts, pts were treated concurrently with prednisone 20 mg/d with a taper over 4 weeks, except in pts in which prednisone was a relative contra-indication. Overall hematologic improvement was determined by MDS IWG 2006 criteria, while hemolytic response was determined to be either a complete normalization (CR) or a partial normalization (PR) if there was &gt;50% improvement in deviation from normal LDH, reticulocytes, indirect bilirubin, or haptoglobin values from baseline. Results: All pts received IVIG administered at 500mg/kg, once weekly, to be spaced out maximally as tolerated. 74% (20/27) of pts received steroids. Baseline characteristics of the pt population: median age of 70 years (range 39-87), representing 21 males and 6 females. Of the pts with MDS evaluable for risk stratification by IPSS-R criteria [n=18], 3 were very low, 5 low, 6 intermediate, 2 high, and 2 very high risk categories. By WHO criteria, the greatest representation was 11/20 RCMD, followed by 3/20 with RAEB2. Baseline cytogenetics [n=21] included 3 pts with very poor, 2 poor, 3 intermediate, 11 good, and 2 very good risk profiles. Pts had a range of 0-6 mutations, most common were SETBP1, ASXL1, TP53 (n=4) and SRSF2, U2AF1, PDGFRB (n=3). 24/27 pts had positive TCR beta and 13/27 had positive TCR gamma gene rearrangements. ORR for any cytopenia was 77.8% (21/27), and for any hemolytic response was 76.2% (16/21). ORR for individual cell lines included: 59.2% (16/27) erythroid, 48.1% (13/27) neutrophil, and 33.3% (9/27) platelet responses. For hemolytic responses, CR/PR rate were measured by LDH (29.6%/11.1%), bilirubin (22.2%/14.8%), retic (33.3%/14.8%), and haptoglobin (22.2%/11.1%). For the 14 MDS pts with very low, low, and intermediate IPSS-R risk, ORR was: 64.3% (9/14) any cytopenia, 35.7% (5/14) erythroid, 50.0% (7/14) neutrophil, 14.3% (2/14) platelets. Combined CR+PR rates for hemolysis in the lower risk categories were 42.9% LDH, 21.4% bili, 42.9% retic, 28.6% haptoglobin responses. For the 5 non-MDS pts, ORR for any cytopenia was 100%, and 60% for any hemolytic response. There were no reported significant adverse events with IVIG administration. Conclusions: IVIG can be used as a first line treatment for pts with autoimmune cytopenias associated with LGL clones and MDS (along with other hematological malignancies). Treatment with IVIG yields an ORR of 77.8% in the entire cohort and 64.3% in pts with lower risk MDS, with a reduction in hemolysis as well. This report expands on a previous analysis and demonstrates further evidence of efficacy for the use of IVIG in treating cytopenias exacerbated by LGL T-cell clones. IVIG therapy can permit a delay in the start of an HMA or IMID treatment, lowering transfusion burden, and increasing ANC to help prevent infectious complications. Further evaluation in a larger cohort of pts is warranted. Studies exploring the mechanism of action are underway. Disclosures Navada: Onconova Therapeutics Inc: Research Funding. Silverman:Onconova Therapeutics Inc: Patents &amp; Royalties, Research Funding; Celgene: Research Funding; Medimmune: Research Funding.

Safety and Efficacy of Atezolizumab in Combination with Rituximab Plus CHOP in Previously Untreated Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Updated Analysis of a Phase I/II Study

Safety and Efficacy of Atezolizumab in Combination with Rituximab Plus CHOP in Previously Untreated Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Updated Analysis of a Phase I/II Study

Dynamics of Activated CD8+ T-cells and Decreased Osteoclasts in the Tumor Microenvironment are Associated with Clinical Efficacy of Anti-PD-L1 and Anti-CD38 Combination Treatment in Relapsed or Refractory Multiple Myeloma

Dynamics of Activated CD8+ T-cells and Decreased Osteoclasts in the Tumor Microenvironment are Associated with Clinical Efficacy of Anti-PD-L1 and Anti-CD38 Combination Treatment in Relapsed or Refractory Multiple Myeloma