Mo In Arm Research Articles

SACI-IO HR+: A randomized phase II trial of sacituzumab govitecan with or without pembrolizumab in patients with metastatic hormone receptor-positive/HER2-negative breast cancer.

LBA1004 Background: Sacituzumab govitecan (SG) is a TROP2 antibody drug conjugate (ADC) with a topoisomerase I inhibitor payload (SN-38) approved for previously treated triple negative and hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (MBC). Double-strand DNA breaks induced by SN-38 activate cGAS-STING, stimulating type I IFN production and T cell recruitment. SN-38 can upregulate MHC class-I and PD-L1 expression, enhance cytotoxic T cell effector functions and deplete regulatory T cells. To evaluate if SG synergizes with pembrolizumab (PD-1 inhibitor) we conducted a randomized, open-label phase 2 study comparing SG with or without pembrolizumab in HR+/HER2- MBC (NCT04448886). Methods: Eligible patients (pts) had unresectable locally advanced or metastatic HR+ (ER≥1% and/or PR≥1%), HER2- breast cancer treated with ≥1 prior endocrine therapy and 0-1 chemotherapy (CT) for MBC. Pts with brain metastases were eligible if locoregional therapy was completed and steroids discontinued ≥7 days before study therapy. Pts who received prior topoisomerase I inhibitor ADC, irinotecan or PD-1/L1 inhibitors were excluded. Pts were randomized 1:1 to Arm A [SG 10 mg/kg IV (D1, D8) + pembrolizumab 200 mg IV (D1), 21-day cycle] or Arm B (SG alone). The primary endpoint was progression-free survival (PFS); secondary endpoints included PFS in PD-L1+ pts (22C3 CPS ≥1), overall survival (OS), objective response rate (ORR) and toxicity (NCI CTCAE v5.0). Baseline and on-treatment biopsies were performed for correlative analyses. For this preliminary analysis, data were locked 1/12/24. Results: Between 03/2021-01/2024, 110 pts enrolled; 104 pts (52 Arm A; 52 Arm B) started study therapy and were included in the analysis. Median age was 57 yrs (range: 27-81); 102 pts (98.1%) were female. 80 pts (76.9%) received prior CDK4/6 inhibitor for MBC; 58 (55.8%) had no prior CT, 46 (44.2%) had 1 prior line of CT for MBC. At a median follow-up of 9.2 months (mo), median PFS was 8.4 mo in Arm A vs 6.2 mo in Arm B (HR 0.76, 95% CI 0.47-1.23, log-rank p=0.26); ORR 21.2% and 17.3%, respectively. OS data are immature with only 26 events to date; OS was 16.9 mo vs 17.1 mo (HR 0.65, 95% CI 0.30-1.41, log-rank p=0.28), respectively. The most frequent treatment-related toxicities (≥G2) in Arm A were neutropenia (67.3%), fatigue (36.5%), alopecia (36.5%), anemia (32.7%), leukopenia (26.9%), diarrhea (21.2%) and nausea (21.2%); in Arm B, neutropenia (59.6%), alopecia (38.5%), diarrhea (34.6%), nausea (32.7%), fatigue (32.7%) and anemia (21.2%). Conclusions: Addition of pembrolizumab to SG showed a non-significant trend toward improved PFS in unselected HR+/HER2- MBC at this preliminary time point. Final PFS and updated OS with further follow-up will be presented at the meeting. Exploratory outcome analyses by TROP2 and PD-L1 expression will be reported. Clinical trial information: NCT04448886 .

Triplet combination treatments with pembrolizumab (pembro) for anti–PD-(L)1–refractory advanced melanoma: Preliminary results of the phase 1/2 KEYMAKER-U02A study.

9506 Background: Anti–PD-(L)1–refractory melanoma is a major challenge, and immunotherapy combination treatment may be useful in this patient population. The phase 1/2 KEYMAKER-U02A (NCT04305041) is a multi-arm, open-label, adaptive umbrella study designed to evaluate pembro + investigational agents for the treatment of anti–PD-(L)1–refractory melanoma. We report results from arm 1 (pembro + quavonlimab [qmab] (anti-CTLA4) + vibostolimab [vibo] (anti-TIGIT)), arm 2 [pembro + qmab + lenvatinib [len] (TKI)), and arm 3 (pembro + ATRA [all-trans retinoic acid]) of KEYMAKER-U02A. Methods: In all arms, adults had stage III/IV melanoma, ≥1 measurable lesion per RECIST v1.1, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and disease progression on anti–PD-(L)1 therapy alone or in combination. Pts were randomized equally to open arms. In arm 1, pts received pembro 200 mg IV Q3W + qmab 25 mg IV Q6W + vibo 200 mg IV Q3W. In arm 2, pts received pembro 400 mg IV Q6W + qmab 25 mg IV Q6W + len 20 mg PO QD. In arm 3, pts received pembro 400 mg IV Q6W + ATRA 150 mg/m2/day PO for 3 days Q3W. Pts received treatment for up to 2 y or until intolerable toxicity, disease progression, or pt withdrawal. Primary end points were safety and ORR per RECIST v1.1 by blinded independent central review (BICR). DOR per RECIST v1.1 by BICR was the secondary end point. PFS per RECIST v1.1 by BICR and OS were exploratory end points. Enrollment was planned for a maximum of 20 pts in each arm and enrollment could continue to up to 40 pts if an ORR of > 20% (5/20) was observed. Enrollment would then continue up to 100 pts if an ORR of ≥35% (14/40) was observed. Results: At data cutoff (Oct 18, 2022), 40 pts had been assigned to arms 1 and 2 and 20 pts to arm 3. Median (range) follow-up was 18.4 (1.7-24.5) mo in arm 1, 18.5 mo (1.6-25.4) in arm 2, and 2.7 mo (0.8-3.5) in arm 3. Efficacy is reported in the table. Treatment-related adverse events (TRAEs) occurred in 35 pts (88%) in arm 1, 38 pts (95%) in arm 2, and 15 pts (75%) in arm 3. Grade 3-5 TRAEs occurred in 11 pts (28%) in arm 1, 23 pts (58%) in arm 2, and 3 pts (15%) in arm 3; 1 pt in arm 2 died from a grade 5 TRAE (immune-mediated nephritis). Conclusions: Although objective responses were observed in some pts with anti–PD-(L)1–refractory melanoma, protocol-prespecified criteria for enrollment expansion were not met in any arm. The safety profile was manageable. Additional arms will be reported for this pt population with a high unmet need. Clinical trial information: NCT04305041 . [Table: see text]

Maintenance therapy with olaparib or selumetinib plus durvalumab (S+D) according to genetic profile of metastatic pancreatic adenocarcinoma (m-PDAC) controlled with modified FOLFIRINOX (mFFX): A phase II randomized MAZEPPA GERCOR D19-02 PRODIGE-72 study.

673 Background: Maintenance treatments in m-PDAC patients (pts) after FFX induction is discussed. We assessed the efficacy of genetic-driven maintenance in pts with controlled disease. Methods: In this multicenter, open-label, phase II study, PS 0-1 pts with histologically confirmed m-PDAC controlled after 4 months (mo) of mFFX received a genetically-driven maintenance therapy (centralized analysis): BRCAness - olaparib 300 mgx2/d (Arm A); no BRCAness, but KRAS mutation - randomization (2:1) to S+D (1500 mg IV q4w + 75 mg PO BID; Arm B) or FOLFIRI q2w (Arm C), until confirmed progression or toxicity. Statistical hypotheses: Arm A, PFS4mo rate after inclusion - H0: PFS4mo ≤40%, H1: PFS4mo ≥70%; Arm B and C, H0: PFSc=PFSb, H1: PFSc<PFSb (one-sided 2.5% α-type I-error and 10% β-type 2). A prespecified single interim analysis for futility using a-spending function with O’Brien-Fleming boundaries was planned after 33.1% of events (~93 pts). The Kaplan-Meier method and a swimmer plot were applied. Results: 124 pts were included in the study; Arm A: 16 pts (male: 9, median age: 67 years, PS 0: 9 pts) received olaparib; PFS 4mo: 50%; median PFS: 3.7 mo (1.7-9.4), ORR: 13%, median OS: 18 mo (5.5-21.5). Arm B/Arm C: at interim analysis (12/5/2022): 104 pts were randomized (Arm B/Arm C: 70/34); median PFS in Arms B and C: 3.5 mo (95% CI 2.1-3.9) vs 5.7 mo (95% CI 2.2-10.7), respectively. Due to futility, inclusions were stopped. At final analysis (data cutoff: 06/15/2023) with median follow up of 11.2 mo (95% Cl 9.4-13.1): 108 pts (male: 53%, age: 63.5 years, PS 0: 44%) were treated (Arm B/Arm C: 72/36). 123/124 pts (ITT population) had ≥1 cycle treatment (median: 4.0 [IQR, 2.0-6.0]). Primary endpoint was not met: median PFS 3.7 mo (95% Cl 2.1-5.0) in Arm B vs 6.6 mo in Arm C (95% Cl 2.6-8.7); HR=1.6 (0.99-2.58), P=0.0523. Median OS (entire population): 12.7 mo (95% CI 8.7-18.2); 10.1 mo (95% CI 8.3-20.6) in Arm B and 17.3 mo (95% CI 8.4-20.9) in Arm C. The toxicity profile: ≥1 grade 3-4 treatment-related arms (A/B/C) was as expected: 18.8%, 23.6%, 28.6% of pts. Conclusions: MAZEPPA study did not meet its primary endpoint of improving PFS4mo in m-PDAC pts treated with S+D maintenance vs those receiving FOLFIRI. Data on genomic alterations analyses will be presented at the congress. Clinical trial information: NCT04348045 .

Abstract CT076: Randomized, global, phase 3 study of tislelizumab plus chemotherapy versus chemotherapy as first-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-306): China subgroup analysis

Abstract Background: Tislelizumab, an anti-programmed cell death protein 1 (PD-1) antibody, + chemotherapy (chemo) demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) vs placebo + chemo, with a manageable safety profile, as a first line (1L) treatment for patients (pts) with advanced or metastatic esophageal squamous cell carcinoma (ESCC) at interim analysis of the phase 3 RATIONALE-306 study. We report data from the China subgroup analysis. Methods: In this randomized, double-blind, global study, adults with unresectable locally advanced or metastatic ESCC, with no prior systemic treatment for advanced disease were enrolled regardless of programmed death-ligand 1 (PD-L1) expression status. Pts were randomized (1:1); stratified by region, prior definitive therapy, and investigator-chosen chemo (platinum + fluoropyrimidine or platinum + paclitaxel). Pts received tislelizumab (T) 200 mg intravenously + chemo (C) (Arm T+C) or placebo (P) + chemo (Arm P+C) once every three weeks; treatment continued until disease progression by investigator per RECIST v1.1, intolerable toxicity, or withdrawal. The primary endpoint was OS in the intent-to-treat (ITT) population. Secondary endpoints included investigator-assessed progression-free survival (PFS) per RECIST v1.1, objective response rate (ORR), and duration of response (DoR), in addition to safety. Results: Of 649 pts in the overall population, 370 (57.0%) were enrolled from China. At data cutoff (Feb 28, 2022), the median study follow-up in the China subgroup (ITT population) was 15.8 months (mo) in Arm T+C (n=182) and 10.6 mo in Arm P+C (n=188). Longer OS (median OS 16.6 mo vs 11.2 mo; unstratified hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.54, 0.89) and PFS (median PFS 8.3 mo vs 5.6 mo; unstratified HR 0.58, 95% CI 0.45, 0.75) indicate survival benefit in Arm T+C vs P+C, respectively. Arm T+C had higher response rates and more durable responses than Arm P+C; ORR was 64.8% vs 44.1% (odds ratio 2.33 [95% CI 1.53, 3.55]) respectively, and median DoR was 7.4 mo (95% CI 5.6, 9.5) vs 5.7 mo (95% CI 4.3, 7.5), respectively. Similar proportions of pts in Arm T+C vs P+C had ≥1 treatment-related adverse event (TRAE; 98.8% vs 98.9%) and ≥grade 3 TRAEs (72.9% vs 73.4%). Serious TRAEs occurred in 27.6% vs 21.2% of pts in Arm T+C vs P+C, and TRAEs leading to death occurred in 2.9% vs 1.6% of pts, respectively. Treatment-emergent adverse events leading to discontinuation occurred in 28.2% vs 17.4%, in Arm T+C vs P+C. Conclusions: In the China subgroup, 1L tislelizumab + chemo demonstrated clinically meaningful improvement in OS, PFS, ORR, and DoR vs placebo + chemo in pts with advanced or metastatic ESCC, with a manageable safety profile, consistent with published results in the overall population. Acknowledgments: This study was sponsored by BeiGene, Ltd. Medical writing support, under the direction of the authors, was provided by Emma Ashman, BSc, of Ashfield MedComms, an Inizio company, and was funded by BeiGene, Ltd. Citation Format: Yongqian Shu, Yueyin Pan, Ping Lu, Yi Jiang, Jingdong Zhang, Xiaohong Wu, Yuanhu Yao, Lin Shen, Yi Ba, Zhiyong He, Yuxian Bai, Jianhua Chen, Guohua Yu, Yanyan Peng, Hongqian Wu, Lei Wang, Liyun Li, Jianming Xu. Randomized, global, phase 3 study of tislelizumab plus chemotherapy versus chemotherapy as first-line treatment for advanced or metastatic esophageal squamous cell carcinoma (RATIONALE-306): China subgroup analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT076.

Final overall survival (OS) analysis of atezolizumab (atezo) monotherapy vs chemotherapy (chemo) in untreated locally advanced or metastatic urothelial carcinoma (mUC) from the Phase 3 IMvigor130 study.

LBA441 Background: Two interim OS analyses from IMvigor130 demonstrated non-statistically significant OS benefit with atezo monotherapy (Arm B) vs placebo + platinum (investigator [INV] choice of carboplatin or cisplatin [carbo or cis])/gemcitabine (plt/gem; Arm C) in patients (pts) with PD-L1–high (IC2/3) mUC, as well as a favorable safety profile vs chemo (Galsky Lancet 2020, Davis AACR 2021). Exploratory data showed clinical benefit with atezo monotherapy in cis-ineligible pts with IC2/3 tumors. Here, we report the final OS analysis from IMvigor130 Arms B and C. Methods: Pts were randomly assigned 1:1:1 to Arm A (atezo + plt/gem; not reported here), B or C. Due to the statistical testing hierarchy, no formal comparison of OS (co-primary endpoint) in Arm B vs C was performed in ITT and IC2/3 pts. ORR and DOR, both per INV-assessed RECIST 1.1 (secondary endpoints), and safety were assessed. Subgroup analyses of OS in cis-ineligible pts and disease control rate (DCR, confirmed CR, PR or [SD ≥6 mo]) were exploratory. Results: As of data cutoff Aug 31, 2022, time since last pt randomly assigned was 49 mo. OS data (Table) did not show benefit for ITT pts, while an HR of 0.56 (0.34, 0.91) was seen in the cis-ineligible IC2/3 subgroup. In the ITT population, the 24-mo OS rates were 34% in Arm B and 32% in Arm C. ORR was 24% (87/359; 38% DCR) in Arm B and 44% (158/356; 59% DCR) in Arm C; median DOR was 29.6 and 8.1 mo, respectively. In cis-ineligible IC2/3 pts, ORR was 40% (20/50) in Arm B and 33% (14/43) in Arm C. Median DOR was not evaluable in Arm B and 6.2 mo in Arm C. Of safety-evaluable pts, 57 of 354 in Arm B (16%) and 312 of 389 in Arm C (80%) had a Gr 3/4 treatment-related AE (TRAE); 3 (1%) and 4 (1%), respectively, had a Gr 5 TRAE. Gr 3/4 AEs of special interest occurred in 36 pts (10%) in Arm B and 17 (4%) in Arm C. Conclusions: The final OS analysis was consistent with previous data. Atezo monotherapy continued to show better tolerability vs chemo with no new safety concerns. These exploratory data support the benefit-risk ratio of atezo monotherapy vs chemo for first-line cis-ineligible IC2/3 mUC. Clinical trial information: NCT02807636 . [Table: see text]

Randomized, global, phase 3 study of tislelizumab (TIS) + chemotherapy (chemo) versus placebo (PBO) + chemo as first-line (1L) treatment for advanced or metastatic esophageal squamous cell carcinoma (ESCC) (RATIONALE-306): Non-Asia subgroup.

340 Background: TIS, an anti-programmed cell death protein 1 (PD-1) antibody, + chemo as 1L therapy demonstrated statistically significant and clinically meaningful improvement in overall survival (OS) vs PBO + chemo in patients with advanced or metastatic ESCC (hazard ratio [HR] 0.66 [95% confidence interval (CI) 0.54, 0.80]; P< 0.0001), with a manageable safety profile, at interim analysis of the phase 3, double-blind RATIONALE-306 study (NCT03783442). Here, we report data from the non-Asia subgroup (Europe, Northern America, and Oceania). Methods: Adults with advanced or metastatic ESCC, with no prior systemic treatment for advanced disease were randomized 1:1, (stratified by region, prior definitive therapy, and investigator [INV]-chosen chemo) to receive TIS 200 mg intravenously (IV) once every 3 weeks (Q3W) (Arm A) or PBO IV Q3W (Arm B), with platinum + fluoropyrimidine, or platinum + paclitaxel until disease progression by INV per RECIST v1.1, intolerable toxicity, or withdrawal. The primary endpoint was OS in the intent-to-treat population. Secondary endpoints included: progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR) by INV per RECIST v1.1; OS in the programmed death-ligand 1 score ≥10%; and safety. Results: Of 649 randomized patients, 163 (25.1%) were from the non-Asia subgroup (Arm A, n = 83; Arm B, n = 80). At data cutoff (Feb 28, 2022), the median study follow-up time in the non-Asia subgroup was 16.0 months (mo) in Arm A vs 8.4 mo in Arm B. OS (median 16.3 vs 9.0 mo; unstratified HR 0.66 [95% CI 0.45, 0.96]) and PFS (median 7.7 vs 5.5 mo; unstratified HR 0.59 [95% CI 0.41, 0.83]) were improved in Arm A vs Arm B, respectively. Arm A had higher ORR (61.4% vs 41.3%, odds ratio 2.27 [95% CI 1.21, 4.25]) and longer median DoR (7.1 mo [95% CI 5.6, 9.6] vs 5.7 mo [95% CI 3.8, 8.3]) than Arm B. More patients in Arm A vs Arm B experienced ≥1 treatment-related adverse event (TRAE; 94.0% vs 88.5%), serious TRAEs (25.3% vs 17.9%), and discontinuation due to treatment-emergent AEs (42.2% vs 35.9%, respectively). Similar proportions of patients in Arm A vs Arm B had ≥grade 3 TRAEs (56.6% vs 52.6%), and TRAEs leading to death (1.2% vs 1.3%), respectively. Conclusions: In the non-Asia subgroup, 1L TIS + chemo showed a clinically meaningful improvement in OS vs PBO + chemo in patients with advanced or metastatic ESCC, with a manageable safety profile, consistent with published results in the overall population. Clinical trial information: NCT03783442 .

Differences in Failure-Free Survival After Salvage Radiotherapy Guided by Conventional Imaging Versus 18F-Fluciclovine PET/CT in Postprostatectomy Patients: A Post Hoc Substratification Analysis of the EMPIRE-1 Trial.

The EMPIRE-1 (Emory Molecular Prostate Imaging for Radiotherapy Enhancement 1) trial reported a survival advantage in recurrent prostate cancer salvage radiotherapy (SRT) guided by 18F-fluciclovine PET/CT versus conventional imaging. We performed a post hoc analysis of the EMPIRE-1 cohort stratified by protocol-specified criteria, comparing failure-free survival (FFS) between study arms. Methods: EMPIRE-1 randomized patients to SRT planning via either conventional imaging only (bone scanning plus abdominopelvic CT or MRI) (arm A) or conventional imaging plus 18F-fluciclovine PET/CT (arm B). Randomization was stratified by prostate-specific antigen (PSA) level (<2.0 vs. ≥ 2.0 ng/mL), adverse pathology, and androgen-deprivation therapy (ADT) intent. We subdivided patients in each arm using the randomization stratification criteria and compared FFS between patient subgroups across study arms. Results: Eighty-one and 76 patients received per-protocol SRT in study arms A and B, respectively. The median follow-up was 3.5 y (95% CI, 3.0-4.0). FFS was 63.0% and 51.2% at 36 and 48 mo, respectively, in arm A and 75.5% at both 36 and 48 mo in arm B. Among patients with a PSA of less than 2 ng/mL (mean, 0.42 ± 0.42 ng/mL), significantly higher FFS was seen in arm B than arm A at 36 mo (83.2% [95% CI, 70.0-91.0] vs. 66.5% [95% CI, 51.6-77.8], P < 0.001) and 48 mo (83.2% [95% CI, 70.0-91.0] vs. 56.2% [95% CI, 40.5-69.2], P < 0.001). No significant difference in FFS between study arms in patients with a PSA of at least 2 ng/mL was observed. Among patients with adverse pathology, significantly higher FFS was seen in arm B than arm A at 48 mo (68.9% [95% CI, 52.1-80.8] vs. 42.8% [95% CI, 26.2-58.3], P < 0.001) though not at the 36-mo follow-up. FFS was higher in patients without adverse pathology in arm B versus arm A (90.2% [95% CI, 65.9-97.5] vs. 73.1% [95% CI, 42.9-89.0], P = 0.006) at both 36 and 48 mo. Patients in whom ADT was intended in arm B had higher FFS than those in arm A, with the difference reaching statistical significance at 48 mo (65.2% [95% CI, 40.3-81.7] vs. 29.1 [95% CI, 6.5-57.2], P < 0.001). Patients without ADT intent in arm B had significantly higher FFS than patients in arm A at 36 mo (80.7% [95% CI, 64.9-90.0] vs. 68.0% [95% CI, 51.1-80.2]) and 48 mo (80.7% [95% CI, 64.9-90.0] vs. 58.6% [95% CI, 41.0-72.6]). Conclusion: The survival advantage due to the addition of 18F-fluciclovine PET/CT to SRT planning is maintained regardless of the presence of adverse pathology or ADT intent. Including 18F-fluciclovine PET/CT to SRT leads to survival benefits in patients with a PSA of less than 2 ng/mL but not in patients with a PSA of 2 ng/mL or higher.

Addition of Niraparib to Best Supportive Care as Maintenance Treatment in Patients with Advanced Urothelial Carcinoma Whose Disease Did Not Progress After First-line Platinum-based Chemotherapy: The Meet-URO12 Randomized Phase 2 Trial

BackgroundPlatinum-based chemotherapy (PBCT) is the standard first-line treatment for advanced urothelial carcinoma (UC). Potential cross-sensitivity can be hypothesized between platinum drugs and poly-ADP ribose-polymerase (PARP) inhibitors. ObjectiveTo compare maintenance treatment with the PARP inhibitor niraparib plus best supportive care (BSC) versus BSC alone in patients with advanced UC without disease progression after first-line PBCT. Design, setting, and participantsMeet-URO12 is a randomized, multicenter, open-label phase 2 trial. Patients with advanced UC, without disease progression after four to six cycles of PBCT, with Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, were enrolled between August 2019 and March 2021. Randomization was stratified by ECOG performance status (0/1) and response to PBCT (objective response/stable disease). InterventionPatients were randomized (2:1) to experimental arm A (niraparib 300 or 200 mg daily according to body weight and baseline platelets, plus BSC) or control arm B (BSC alone). Outcome measurements and statistical analysisThe primary endpoint was progression-free survival (PFS). The analysis was performed on an intention-to-treat basis. The secondary endpoints reported in this primary analysis are progression-free rate at 6 mo and safety (adverse event rate). Results and limitationsFifty-eight patients were randomized (39 in arm A and 19 in arm B). The median age was 69 yr, ECOG performance status was 0 in 66% and 1 in 34%; and the best response with chemotherapy was objective response in 55% and stable disease in 45%. The median PFS was 2.1 mo in arm A and 2.4 mo in arm B (hazard ratio 0.92; 95% confidence interval 0.49–1.75, p = 0.81). The 6-mo progression-free rates were 28.2% and 26.3%, respectively. The most common adverse events with niraparib were anemia (50%, grade [G]3 11%), thrombocytopenia (37%, G3–4 16%), neutropenia (21%, G3 5%), fatigue (32%, G3 16%), constipation (32%, G3 3%), mucositis (13%, G3 3%), and nausea (13%, G3 3%). The main limitation of the study is the small sample size: in March 2021, approval of maintenance avelumab for the same setting rendered randomization of patients in the control arm to BSC alone unethical, and accrual was stopped prematurely. ConclusionsAddition of maintenance niraparib to BSC after first-line PBCT did not demonstrate a significant improvement in PFS in patients with UC. These results do not support the conduction of a phase 3 trial with single agent niraparib in this population. Patient summaryIn this trial, we tested the efficacy of niraparib as maintenance treatment in patients affected by advanced urothelial cancer after the completion of first-line chemotherapy. We could not demonstrate a significant improvement in progression-free survival with maintenance niraparib.

Evaluating the Impact of Prostate Only Versus Pelvic Radiotherapy for Pathological Node-positive Prostate Cancer: First Results from the Multicenter Phase 3 PROPER Trial

BackgroundThe optimal treatment for patients with pathological node-positive (pN1) prostate cancer (PCa) is unclear. ObjectiveTo evaluate whether whole-pelvis radiotherapy (WPRT) improves clinical relapse-free survival (cRFS) in comparison to prostate-only radiotherapy (PORT) in pN1 PCa. Design, setting, and participantsPROPER was a phase 3 trial randomizing patients to WPRT or PORT. All patients had pN1cM0 PCa with fewer than five lymph nodes involved. InterventionAll patients underwent pelvic lymph node dissection followed by radical prostatectomy/primary radiotherapy + 2 yr of androgen deprivation therapy (ADT). Patients were randomized to PORT (arm A) or WPRT (arm B). Outcome measurements and statistical analysisThe primary outcome was cRFS. The secondary endpoints were overall survival (OS), biochemical relapse–free survival (bRFS), and toxicity. The study was stopped because of poor accrual in June 2021 after the inclusion of 69 patients. We report on OS, bRFS, cRFS, and acute and late toxicity. Results and limitationsThe median follow-up was 30 mo in arm A (n = 33) and 36 mo in arm B (n = 31). The 3-yr OS rate was 92% ± 5% in arm A and 93% ± 5% in arm B (p = 0.61). None of the patients died of PCa. The 3-yr bRFS was 79% ± 9% in arm A and 92% ± 5% in arm B (p = 0.08). The 3-yr cRFS rate was 88% ± 6% in arm A and 92% ± 5% in arm B (p = 0.31). No pelvic recurrence was observed in arm B. Acute grade 2 gastrointestinal toxicity was higher with WPRT (15% in arm A vs 45% in arm B; p = 0.03). Limitations are the early closure because of poor accrual and the limited follow-up. ConclusionsThe results of our trial are hypothesis-generating but add evidence supporting the recommendation to offer WPRT to patients with pN1 PCa. However, WPRT is associated with more acute gastrointestinal toxicity. Patient summaryWe looked at the impact of radiotherapy to the whole pelvis (WPRT) for patients with prostate cancer that had spread to the lymph nodes. Although the trial was closed early because of poor enrolment, we found that WPRT improves survival free from relapse, and no recurrences were observed in the pelvis. WPRT is associated with more acute side effects on the gastrointestinal system in comparison to radiotherapy to just the prostate.

A randomized phase II/ III trial of nivolumab versus nivolumab plus docetaxel for previously treated advanced or recurrent non–small cell lung cancer: TORG1630.

9030 Background: Immuno-checkpoint inhibitor (ICI) monotherapy is a standard second-line treatment for non-small-cell lung cancer (NSCLC). Addition of a cytotoxic agent to ICI may enhance the benefits. Methods: This multi-institutional open-label randomized phase II/III study compared the arm A consisting of nivolumab (NIV) monotherapy and arm B consisting of NIV + docetaxel (DTX) for patients with previously treated ICI-naïve NSCLC, prestratified by PS/histological types/sex/driver-mutations. The primary endpoint was superiority of arm B in OS in the phase III part. Assuming a HR of 0.75 for OS with the estimated mOS of arm A/B as 10.5/14.0 mo, a total 350 patients would be required to provide 80% power at a one-sided α of significance being 0.05. It was started at Nov. 2017, however, the patients’ accrual was discontinued due to the approval of ICI in the first-line setting in late 2018. Eventually, a total of 131 patients were enrolled for analysis. Results: 128 patients (64 in each arm) were eligible and included in full analysis set (FAS), and the patients’ demographics were well-balanced in each arm. The mOS was 14.7 mo (95%CI, 11.4-18.7) in arm A, and 23.1 mo (95%CI, 16.7-NR) in arm B. The HR of OS was 0.63 (90%CI, 0.42-0.95; p = 0.0310). The mPFS was 3.1 mo (95%CI, 2.0-3.9) and 6.7 mo (95%CI, 3.8-9.4) in arm A and B, respectively. The HR for PFS was 0.58 (95%CI, 0.39-0.88; p = 0.0095). The ORR was 14.0% (95%CI, 6.3-25.8) in arm A, and 41.8% (95%CI, 28.7-55.9) in arm B, with a statistical significance (p = 0.0014). Subgroup analyses for OS disclosed that the HRs favored arm B over arm A across all prespecified subgroups. The mOS of EGFR-mutant subgroup also showed better tendency in arm B than A (11.0 mo in arm A; 95%CI, 3.5-14.0; vs 20.6 mo in B; 95%CI, 5.8-NR; HR 0.45; 95%CI, 0.17-1.17). The hematological toxicity and gastrointestinal adverse events were more common in arm B than in A. Six (9.4%) in arm A and 25 patients (39.1%) in arm B discontinued protocol treatment due to adverse events. Overall, two treatment-related deaths were observed; one from pneumonitis in arm A, and one from myocarditis in arm B. Conclusions: Although the resulting statistical power was limited because of reduced sample size, the addition of DTX to NIV in the second-line NSCLC therapy significantly improved OS, PFS, and ORR, despite slightly elevated risk of toxicity. This is the first randomized clinical trial that confirmed significant survival benefit of ICI + chemotherapy over ICI alone in any cancer type. Clinical trial information: UMIN000021813.

Phase II randomized double blind trial of axitinib (Axi) +/- PF-04518600, an OX40 antibody (PFOX) after PD1/PDL1 antibody (IO) therapy (Tx) in metastatic renal cell carcinoma (mRCC).

4529 Background: Immune checkpoint blockade has revolutionized mRCC Tx, but primary and acquired resistance continues to result in poor patient outcomes. OX40 (CD-134) mediates IO resistance. Co-stimulatory OX40 (CD-134) activates exhausted T-cells. OX40 activation in dendritic cells increases the proliferation, effector function, and survival of T cells. PFOX is an agonist for OX40. We hypothesized that PFOX + the VEGFR inhibitor Axi would improve outcomes vs. Axi in patients (pts) with mRCC after IO Tx. Methods: Pts with predominantly clear cell mRCC were stratified for MSKCC risk groups then randomized 1:1 to Axi 5mg po bid plus PFOX 0.3mg/kg iv (Arm 1) or placebo (PL) iv (Arm 2) on Day 1 of a 2-week cycle. The primary endpoint was progression free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR) per RECIST v1.1, and safety/tolerability. A prespecified interim analysis (IA) tested PFS at a 1-sided P &lt; 0.02 when ≥ 33 events were observed. Results: Between February 2018 and October 2021 a total of 59 pts were randomly assigned and treated with Axi+PFOX (N = 29) or Axi+PL (N = 30). Pt and disease characteristics are summarized in the table. As of October 2021, 38 PFS events had occurred, 19 on each arm. The IA rejected the hypothesis of added efficacy for PFOX with a p of 0.0089. Subsequently the study was closed to new accrual. At a median follow up of 13.4 mo, median PFS was 13.1 (6-15.8) months (mo) for Arm 1 and 8.5 (5.5-11) mo for Arm 2 (HR = 0.85 [95% CI: 0.45-1.60] p = 0.61). After adjusting by MSKCC risk group and prior lines of Tx, HR = 0.74 [95% CI: 0.38-1.46] p = 0.39. Median OS was not reached (adjusted HR = 0.71 [95% CI: 0.24-2.12] p = 0.54). ORR Arm 1: 31% PR, 52% SD, 14% PD, and Arm 2: 37% PR, 50% SD, 13% PD. Median DOR 9.1 (3.3-23.9) mo for Arm 1, and 7.5 (1.8-32.7) mo. for Arm 2. Rates of any grade Tx related adverse events (TRAEs; 93% vs 100%), including grade 3 or 4 TRAEs (66% vs 47%), in Arm 1 and Arm 2, respectively. 4 pts discontinued Tx due to TRAE, 3 in Arm 1 (1 grade 3 hypertension, 1 grade 2 stroke, 1 grade 3 bullous dermatitis) and 1 in Arm 2 (grade 4 ALT elevation). The most common TRAEs were diarrhea 52%, hypertension 52%, fatigue 41%, nausea 41% for Arm 1 and hypertension 67%, diarrhea 53%, fatigue 50% for Arm 2. Conclusions: In IO-pretreated mRCC pts, Axi + PFOX did not improve outcomes compared to Axi alone. Clinical trial information: NCT03092856. [Table: see text]

A phase 1 first-in-human study of the anti-LAG-3 antibody MK4280 (favezelimab) plus pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer.

3584 Background: Patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) that progressed on ≥2 prior therapies have limited treatment options, with median OS ranging from 6-9 months (mo). In the dose-escalation phase of this first-in-human multicohort study (NCT02720068), the anti-lymphocyte activation gene (LAG)-3 antibody favezelimab (fave) was well tolerated alone and with pembrolizumab (pembro) across all dose levels (Lakhani, SITC, 2018, abstract O26). Here, we evaluate the safety and efficacy of fave alone or in combination with pembro in pts with advanced MSS CRC from the dose confirmation phase. Methods: Eligible pts with MSS PD-1/PD-L1-treatment-naïve mCRC that progressed on prior standard-of-care (3L+) were enrolled (cohort A) to receive the RP2D of 800 mg fave alone (Arm 1), 800 mg fave + 200 mg pembro (Arm 2C), or 800 mg fave + 200 mg pembro (MK-4280A) co-formulation (Arm 5), all Q3W. Treatment continued for 35 cycles or until progression, unacceptable toxicity, or investigator/pt decision. Pts with confirmed progression per irRECIST v1.1 on fave alone could crossover to 800 mg fave + pembro. Safety was assessed in all treated pts; efficacy in the full analysis set (FAS) of all treated pts with baseline scan. Objectives included safety (primary), ORR (RECIST v1.1 by investigator [secondary]), and DOR, PFS, and OS (exploratory). Interim analysis data cut-off was: Oct. 23, 2020. Results: A total of 20 pts received fave (Arm 1); 89 pts (including 9 crossover) received fave + pembro (Arms 2C+5); 12 pts (Arm 1) and 36 pts (Arms 2C+5), had PD-L1 CPS ≥1 tumors. At data cut-off, median follow-up was 5.8 months (mo) in Arm 1 and 6.2 mo in Arms 2C+5. Treatment-related adverse events (TRAEs) were 65% with fave (Arm 1) and 65.2% with fave + pembro (Arms 2C+5). Grade ≥3 TRAEs were 15% (Arm 1), and 20% [Arms 2C+5]). No grade 5 TRAEs were reported. Common TRAEs (≥15%) included fatigue (20.0%), nausea (15%) with fave, and fatigue (16.9%) with fave + pembro. Confirmed ORR was 6.3% (4PR, 1CR) with fave + pembro (Arms 2C+5). No pt receiving fave alone responded. In Arms 2C+5, median DOR was 10.6 mo (range, 5.6-12.7). ORR, OS and PFS by PD-L1 status are reported in the Table. Conclusions: Favezelimab alone or in combination with pembrolizumab had a manageable safety profile, with no treatment-related deaths. Promising antitumor activity was observed with combination therapy, including with MK-4280A, compared with monotherapy most notably in pts with PD-L1 CPS ≥1 tumors. Clinical trial information: NCT02720068. [Table: see text]

A phase 2 study of berzosertib (M6620) in combination with carboplatin compared with docetaxel in combination with carboplatin in metastatic castration-resistant prostate cancer.

5034 Background: Alterations in DNA damage repair (DDR) genes are common in metastatic castration-resistant prostate cancer (mCRPC), and are implicated in responses to carboplatin [carbo], PARP inhibitors and immunotherapeutics. Inhibitors of the ATR kinase, which is involved in the DDR response, have been demonstrated to have synergistic activity with platinum compounds in preclinical models. We therefore conducted a phase 2 study of the ATR inhibitor berzosertib [berzo]+carbo vs. docetaxel [doce]+carbo in mCRPC. Methods: Patients (pts) previously treated with at least one secondary hormonal therapy and taxane underwent mandatory pre-treatment biopsy and were randomized 1:1 to receive Arm A (doce 60 mg/m2 day 1 + carbo AUC 4 day 1) or Arm B (berzo 90 mg/m2 days 2,9 + carbo AUC 5 day 1) every 21 days. Pts randomized to Arm A who were not candidates for doce received carbo AUC 5 monotherapy. Stratification factors were 1) prior PARP inhibitor (yes vs. no) and 2) evaluable disease by RECIST 1.1 (yes vs. no). Pts on Arm A crossed over to Arm B (berzo+carbo) at the earlier of PSA or radiographic progression. The primary endpoint was overall response rate (ORR; PSA reduction by ≥ 50% or radiographic response by RECIST 1.1). Secondary endpoints included time to PSA progression, radiographic PFS (rPFS), PFS by PCWG3 criteria, and adverse events (AEs) in each arm. Planned enrollment was 136 pts (for 130 to be treated), with interim analysis for futility after 65 pts were treated. Results: 73 pts were randomized between 6/2019 and 7/2020; 34 pts were treated on Arm A (26 carbo+doce; 8 carbo alone) and 31 on Arm B. Median number of prior systemic therapies (excluding ADT, 5α-reductase inhibitors, 1st generation antiandrogens) was 4 (range 2-8). Median treatment duration was 3 cycles, and 4 pts in each arm discontinued for AEs. Grade 3 or higher treatment-related AEs (TrAE) were seen in 13(38%) pts in Arm A and 21(68%) in Arm B. Pts in Arm B had greater frequency of grade 3-4 thrombocytopenia (8[26%] vs. 3[9%]). 1 pt in Arm B had grade 5 sepsis attributed to study treatment. ORR was 15% in Arm A (5/34; 5/26[19%] in pts who received carbo+doce) and 0% in Arm B (0/31). 14 pts in Arm A crossed over, with no subsequent responses seen. Median rPFS was 2.1(95% CI:2.0,3.2) mo in Arm A and 2.4(1.9,4.2) mo in Arm B. At planned interim analysis, trial enrollment and crossover to Arm B were halted due to futility. Conclusions: Carbo+berzo led to fewer overall responses and a higher rate of grade 3 or higher TrAEs compared to carbo+doce. All responses seen were in pts who received carbo+doce despite requirement for prior progression on taxane, suggesting that this combination is favored over carbo+berzo or carbo monotherapy in a heavily pre-treated biomarker-unselected population. Extensive genetic and molecular studies for DDR assessment from tissue and cfDNA are in progress. Clinical trial information: NCT03517969.

Nivolumab (NIVO) plus ipilimumab (IPI) combination therapy in patients (Pts) with advanced hepatocellular carcinoma (aHCC): Long-term results from CheckMate 040.

269 Background: NIVO 1 mg/kg + IPI 3 mg/kg Q3W (4 doses) followed by NIVO 240 mg Q2W is approved in the US for sorafenib-treated pts with aHCC based on initial results from CheckMate 040 (NCT01658878), which reported objective response rate (ORR) of 32% and median overall survival (mOS) of 22.8 months (mo).1 We present 44-mo long-term follow-up results from the CheckMate 040 NIVO+IPI cohort. Methods: Pts were randomized to 3 arms: [A] NIVO 1 mg/kg + IPI 3 mg/kg Q3W (4 doses) or [B] NIVO 3 mg/kg + IPI 1 mg/kg Q3W (4 doses), each followed by NIVO 240 mg Q2W, or [C] NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W. Treatment continued until intolerable toxicity or disease progression. Safety and tolerability, ORR (blinded independent central review per RECIST v1.1), duration of response (DOR), disease control rate (DCR), and OS were assessed. Data cutoff was May 26, 2020. Results: 148 pts were randomized. Minimum follow-up was 44 mo. mOS remained at 22.2 mo in arm A, 12.5 mo in arm B, and 12.7 mo in arm C; 36-mo OS rates were 42%, 26%, and 30%, respectively. Durable responses were achieved across treatment arms, with DOR approaching 4 years in some cases. DCR was higher in arm A than arms B and C. In all arms, responses were observed regardless of baseline programmed death ligand 1 expression ( &lt; 1% or ≥ 1%) or baseline alpha-fetoprotein level ( &lt; 400 µg/L or ≥ 400 µg/L). Pts with hepatitis B or C virus (HBV or HCV) etiology had higher ORR than uninfected pts in arms B (29% vs 43% vs 9%) and C (31% vs 42% vs 0%). ORR was independent of etiology in arm A (HBV, 32%; HCV, 29%; uninfected, 31%). Additional efficacy data are in the table. There were no additional discontinuations due to treatment-related adverse events or immune-mediated adverse events (IMAEs) since the primary analysis. IMAEs were reported more frequently in arm A than arms B and C; the most common were rash, hepatitis, and adrenal insufficiency. Most IMAEs were reversible and resolved when treated using established algorithms. Conclusions: At a minimum follow-up of 44 mo, second-line NIVO1+IPI3 continued to demonstrate clinically meaningful responses and long-term survival benefit in aHCC. The safety profile was manageable and no new safety signals were identified with longer follow-up. Clinical trial information: NCT01658878. [Table: see text]

Alliance A021501: Preoperative mFOLFIRINOX or mFOLFIRINOX plus hypofractionated radiation therapy (RT) for borderline resectable (BR) adenocarcinoma of the pancreas.

377 Background: Neoadjuvant therapy has been associated with a median overall survival (OS) of 18 – 23 months (mo) in patients (pts) with BR pancreatic ductal adenocarcinoma (PDAC). To establish reference regimens to which novel treatments can be compared in future studies, we evaluated neoadjuvant mFOLFIRINOX with or without RT in BR PDAC in a phase II National Clinical Trials Network (NCTN) trial. Methods: Pts with ECOG PS 0-1 and BR PDAC confirmed by central real-time radiographic review after pre-registration were randomized to either arm A: 8 cycles of neoadjuvant mFOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 over 46 hours), or arm B: 7 cycles of mFOLFIRINOX followed by stereotactic body RT (SBRT, 33-40 Gy in 5 fractions [fx]) or hypofractionated image guided RT (HIGRT, 25 Gy in 5 fx). Pts in either arm without disease progression underwent pancreatectomy, then 4 cycles of adjuvant mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 and infusional 5-fluorouracil 2400 mg/m2 over 46 hours). The primary endpoint, 18-mo OS rate, of each arm was compared to a historical control of 50%. Planned interim analysis mandated closure of either arm in which &lt;11 of first 30 accrued pts underwent R0 resection. Results: 155 pts pre-registered and 126 pts were enrolled to arm A (N=70; 54 randomized, 16 following closure of arm B) or arm B (N=56; closed at interim analysis, all pts randomized prior to closure). Median age (A: 63y, B: 67y), median CA 19-9 level (A: 171 U/ml, B: 248 U/ml) and ECOG PS (A: 51% PS 0, B: 57% PS 0) of registered pts were similar between arms (p &gt; 0.05). Treatment detailed in Table. The 18-mo OS rate based on Kaplan Meier estimates was 67.9% (95%CI: 54.6 – 78.0) in arm A and 47.3% (95%CI: 33.7 – 59.7) in arm B. Among pts who underwent pancreatectomy, 18-mo OS rate was 93.1% (95%CI: 84.3 – 100) and 78.9% (95%CI: 62.6 – 99.6) in arm A and B, respectively. With median follow-up of 27 and 31 mo, median OS was 31.0 (95%CI: 22.2 – NE) mo and 17.1 (95%CI: 12.8 – 24.4) mo in arm A and B, respectively. Conclusions: Neoadjuvant mFOLFIRINOX was associated with favorable OS relative to historical data in pts with BL PDAC in this phase II NCTN trial. mFOLFIRINOX with hypofractionated RT did not improve OS compared to historical data. mFOLFIRINOX represents a reference regimen in this setting and a backbone on which to add novel agents. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org Clinical trial information: NCT02839343. [Table: see text]

Efficacy of Chemotherapeutic Regimens for Mantle Cell Lymphoma: A Systematic Review of Phase III Trials

Background: The mainstay treatment for mantle cell lymphoma (MCL) is chemotherapy ± immunotherapy. The standard chemotherapeutic regimens have limited efficacy in MCL when used alone. In this systematic review, we have assessed the efficacy and safety of various combination regimens for the treatment of MCL evaluated in phase III clinical trials. Methods: We performed a comprehensive systematic literature search on PubMed, Embase, clinicaltrials.gov, and Web of Science databases with the date of inception to May 2020. We used MeSH (Medical Subject Headings) terms for "mantle cell lymphoma", "treatment outcome" along with their keywords, and combined their results. Our search generated a total of 3572 articles. After excluding case reports, case series, observational studies, review articles, meta-analysis, phase I/II clinical trials, and pre-clinical studies, we included five phase III randomized clinical trials (RCTs) reporting the efficacy of combination regimens for MCL treatment. Results Data from five phase III RCTs was pooled with total N=1683 (newly diagnosed (ND), n=1242, relapsed/refractory (RR), n=441). 1610 patients were evaluable. Kluin-Nelemans et al. 2020 (n=560) studied induction with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) vs R-FC (rituximab, fludarabine, and cyclophosphamide) for ND-MCL with follow-up on maintenance with rituximab (R) -vs interferon alfa. At a median follow up of 7.6 years (y), median overall survival (mOS) was 6.4 vs 3.9 y (p=0.0054) in R-CHOP vs R-FC group, respectively. The median progression-free survival (mPFS) and mOS in the R-CHOP cohort on R maintenance were significantly better when compared to those on interferon alfa maintenance (mPFS, 5.4 y vs 1.9 y, p&amp;lt;0.001) (mOS, 9.8 y vs 7.1 y, p=0.0026). Robak et al. (2015) (n=487) assessed bortezomib in ND-MCL by substituting it for vincristine in the standard R-CHOP therapy. A cohort of MCL ineligible for stem cell transplant (SCT) was randomly assigned to either R-CHOP or VR-CAP (bortezomib replacing vincristine). At a median follow-up of 40 months (mo), mPFS was 24.7 mo vs 14.4 mo in VR-CAP vs R-CHOP (HR 0.63, p&amp;lt;0.001), respectively. Similar, relative improvements were reported in complete response (CR) (53% vs 42%, p=0.007) and 4-year OS was (64% [95% CI 56-71] vs 54% [95% CI 45-62]). Jin et al. (2018) (n=121) assessed R-CHOP vs VR-CAP in ND-MCL patients ineligible for SCT. After a median follow-up of 42.4 mo, mPFS for VR-CAP was better than R-CHOP (28.6 mo vs 13.9 mo, HR=0.7, p=0.157). The overall response rate (ORR) was almost similar in VR-CAP (97%) and R-CHOP (98%). The 4-year OS was 62% vs 61% in VR-CAP vs R-CHOP, respectively. Flinn et al. (2014) (n=74) studied the efficacy of bendamustine in combination with rituximab (BR) vs R-CHOP or R-CVP (R-CHOP minus doxorubicin) as induction regimens in ND-MCL. 36 patients received BR and 38 patients received R-CHOP/R-CVP. ORR was 94% vs 85% with BR vs R-CHOP/R-CVP, respectively. Hess et al. (2009) (n=162) evaluated temsirolimus in RR-MCL. The study population was randomized to either 175/75mg temsirolimus (arm A), 175/25mg temsirolimus (arm B), and the investigator's choice of chemotherapy (arm C). The mPFS was significantly better in arm A compared to arm C (4.8 mo vs 1.9 mo, HR 0.44 [97.5% CI 0.25-0.7], p=0.0009). Arm B had slight improvement but insignificant. Similarly, mOS was 12.8 mo in arm A (HR 0.8 [95% CI 0.5-1.28], p=0.35), and 8.8 in arm B (HR 0.96 [95% CI 0.60-1.54], p=0.87), when compared to 9.5 mo in arm C. Drelying et al. (2016) (n=280), studied temsirolimus in comparison with ibrutinib, RR-MCL with mPFS of 14.6 mo (95% CI 10.4-not estimable) vs 6.2 mo (95% CI 4.2-7.9), respectively. Toxicities were typically manageable. VR-CAP was associated with a higher incidence of toxicity (100%) vs R-CHOP (94%) majority of which was hematological. Thrombocytopenia was particularly more prominent with temsirolimus. Granulocytopenia was persistent in 30-40% in the R-FC cohort after 5 y. Conclusion: The chemo-immunotherapy combination is favorable compared to chemotherapy alone for the treatment of MCL. R-CHOP induction followed by rituximab maintenance in MCL shows favorable long-term safety and efficacy profile. Bortezomib substituting for vincristine in R-CHOP improves the efficacy outcomes. Ibrutinib-based regimens are superior to temsirolimus-based regimens. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

LBA65 The Canadian Cancer Trials Group PA.7 trial: Results of a randomized phase II study of gemcitabine (GEM) and nab-paclitaxel (Nab-P) vs GEM, nab-P, durvalumab (D) and tremelimumab (T) as first line therapy in metastatic pancreatic ductal adenocarcinoma (mPDAC)

GEM and Nab-P is a standard first line therapy for mPDAC based on the MPACT Trial. D is a human monoclonal antibody (mAb) that inhibits binding PD-L1 to its receptor. T is a mAb directed against CTLA-4. PA.7 is designed to evaluate whether combining PD-L1 and CTLA-4 inhibition with GEM and Nab-P increases treatment efficacy. This randomized phase II study (NCT02879318) assessed the efficacy and safety of GEM, Nab-P, D, and T (arm A) vs GEM and Nab-P (arm B) in patients (pts) with mPDAC (n=191). Pts with untreated mPDAC and good performance status (ECOG PS 0-1) were eligible. A safety run in was conducted for 11 pts receiving GEM, Nab-P, D and T. The study then randomized 180 pts in a 2:1 ratio to receive GEM (1000mg/m2 D1, 8, 15); Nab-P (125mg/m2 D1, 8, 15); D (1500 mg) D1 q 28 days and T (75 mg) D1 for first 4 cycles vs. GEM and Nab-P alone. The primary endpoint is overall survival (OS); secondary endpoints include progression free survival (PFS), safety, overall response rate (ORR) and quality of life. 180 pts were randomized (119 to arm A and 61 to arm B) between April 2017 and July 2018. Baseline characteristics were well balanced. With a median (med) follow-up of 28.5 months (mo) there was no significant difference in OS (med 9.8 mo in arm A vs. 8.8 mo in arm B, Hazard Ratio (HR)=0.94, 90% confidence interval (CI) 0.71-1.25, p=0.72). There was no significant difference in PFS (med 5.5 mo vs 5.4 mo respectively, HR=0.98, 90% CI 0.75-1.29, p=0.91). ORR was not significantly different, 30.3% vs. 23.0% respectively (Odds Ratio=1.49, 90% CI 0.81-2.72, p=0.28). Disease control rate (DCR) was 70.6% vs 57.4% respectively (difference=13.2%, 90% CI 0.7-25.7%, p=0.096). The only significant difference in grade 3 or greater adverse events was lymphopenia (38% vs 20% respectively, p=0.02). The addition of dual immune checkpoint inhibitors to Gem and Nab-P did not result in a significant improvement in OS, PFS, or ORR. There is a trend to improved DCR. Correlative analyses to assess biomarkers that may predict immune sensitivity in this setting are underway.

Abstract CT216: IMpower150 final analysis: Efficacy of atezolizumab (atezo) + bevacizumab (bev) and chemotherapy in first-line (1L) metastatic nonsquamous (nsq) non-small cell lung cancer (NSCLC) across key subgroups

Abstract Background: The Ph III IMpower150 study (NCT02366143) showed PFS and OS benefit with atezo + bev + carboplatin (carbo) + paclitaxel (pac; ABCP; Arm B) vs bev + carbo + pac (BCP; Arm C) as 1L treatment (tx) for patients (pts) with metastatic nsq NSCLC. Clinical benefit was also seen in pts with EGFR-mutant or ALK-positive (EGFR/ALK+) tumors. We report the final efficacy analyses from IMpower150, including those of the experimental tx arm evaluating atezo + carbo + pac (ACP; Arm A) vs Arm C. Methods: The randomized, open-label, Ph III IMpower150 study evaluated ACP (Arm A) or ABCP (Arm B) vs BCP (Arm C) in pts with metastatic nsq NSCLC (N = 1202). Key eligibility criteria included no prior chemotherapy, measurable disease per RECIST 1.1 and ECOG PS 0-1. Pts were stratified by sex, baseline liver metastases (mets) and PD-L1 expression. Coprimary endpoints were investigator-assessed PFS and OS in ITT wild-type (WT; no EGFR or ALK genetic alterations) pts. Secondary endpoints included PFS and OS in the ITT and PD-L1 expression subgroups. Results: With a minimum follow-up of 32.4 mo (data cutoff: Sep 13, 2019), median OS in ITT-WT pts was 19.0 mo in Arm A vs 14.7 mo in Arm C (HR, 0.84; 95% CI: 0.71, 1.00; Table). OS improvement in the TC1/2/3 or IC1/2/3-WT PD-L1 subgroup was seen in Arm A vs C; no improvement was seen in the TC0 and IC0-WT subgroup. In pts with EGFR/ALK+ tumors and pts with baseline liver mets, OS was comparable in Arms A and C; continued OS benefit in these subgroups was seen in Arm B vs C. The safety profile of each regimen was consistent with previously reported data at the second interim OS analysis (data cutoff: Jan 22, 2018). Arm A vs Arm CArm B vs Arm CaOS HR (95% CI)Median OS, moOS HR (95% CI)Median OS, moITTb (n = 402 [Arm A]; 400 [Arm B]; 400 [Arm C])0.86 (0.73, 1.01)19.0 vs 15.00.80 (0.68, 0.95)19.8 vs 15.0ITT-WTb (n = 350 [Arm A]; 359 [Arm B]; 338 [Arm C])0.84 (0.71, 1.00)19.0 vs 14.70.80 (0.67, 0.95)19.5 vs 14.7TC1/2/3 or IC1/2/3-WT (n = 185 [Arm A]; 192 [Arm B]; 165 [Arm C])0.71 (0.55, 0.91)24.4 vs 16.00.73 (0.57, 0.94)22.5 vs 16.0TC0 and IC0-WT (n = 164 [Arm A]; 167 [Arm B]; 173 [Arm C])0.96 (0.76, 1.22)14.8 vs 14.10.90 (0.71, 1.14)16.9 vs 14.1EGFR/ALK+ (n = 52 [Arm A]; 41 [Arm B]; 62 [Arm C])1.03 (0.67, 1.58)21.2 vs 17.50.77 (0.48, 1.26)25.3 vs 17.5EGFR sensitizing (n = 33 [Arm A]; 26 [Arm B]; 32 [Arm C])1.00 (0.57, 1.74)19.0 vs 18.10.60 (0.31, 1.14)29.4 vs 18.1Liver mets ITT (n = 52 [Arm A]; 52 [Arm B]; 57 [Arm C])1.01 (0.68, 1.51)7.7 vs 9.10.67 (0.45, 1.02)13.2 vs 9.1IC, tumor-infiltrating immune cells; TC, tumor cells. TC1/2/3 or IC1/2/3 = TC ≥ 1% or IC ≥ 1% PD-L1. TC0 and IC0 = TC &amp;lt; 1% and IC &amp;lt; 1% PD-L1.aAnalysis considered final at second OS interim analysis; data shown are for descriptive purposes only.bStratified analysis. Conclusions: At the final OS analysis, IMpower150 showed numerically but not statistically significant OS improvement in Arm A vs C. Final analysis data from IMpower150 continue to show OS benefit with 1L ABCP in nsq NSCLC, including in key subgroups (sensitizing EGFR mutations, liver mets). Citation Format: Mark A. Socinski, Tony S. Mok, Makoto Nishio, Robert M. Jotte, Federico Cappuzzo, Francisco Orlandi, Daniil Stroyakovskiy, Naoyuki Nogami, Delvys Rodriguez-Abreu, Denis Moro-Sibilot, Christian A. Thomas, Fabrice Barlesi, Gene Finley, Shengchun Kong, Xiaoyan Liu, Anthony Lee, Shelley Coleman, Geetha Shankar, Martin Reck. IMpower150 final analysis: Efficacy of atezolizumab (atezo) + bevacizumab (bev) and chemotherapy in first-line (1L) metastatic nonsquamous (nsq) non-small cell lung cancer (NSCLC) across key subgroups [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT216.

IMvigor130 clinical trial in patients (pts) with metastatic urothelial carcinoma (mUC): Analysis of upper tract (UT) and lower tract (LT) subgroups.

551 Background: IMvigor130 demonstrated a statistically significant improvement in PFS in pts receiving atezolizumab (atezo; anti–PD-L1) + platinum-based chemotherapy (plt/gemcitabine [gem]; Arm A) vs placebo + plt/gem (Arm C) as first-line treatment for mUC (Grande et al. 2019). Exploratory analyses examined efficacy outcomes in UT and LT mUC subgroups. Methods: Pts with UT and LT mUC from Arm A and Arm C were included. Chemotherapy was gem + investigator choice of plt (cisplatin or carboplatin). Tumors were assessed at baseline and every 9 wk until investigator-assessed PD per RECIST 1.1 or other events. PFS, OS and ORR in UT and LT subgroups are shown. Results: Baseline characteristics were comparable between Arm A and Arm C in the UT and LT subgroups; however, slight imbalances were noted, such as higher PD-L1–positive status (IC2/3) and lower Bajorin risk score in UT Arm A pts. With a median follow-up of 11.8 mo, median PFS was8.2 vs 6.2 mo in Arm A vs Arm C in UT pts (HR, 0.69 [95% CI: 0.51, 0.94]) and 8.1 vs 6.5 mo, respectively, in LT pts (HR, 0.85 [95% CI: 0.70, 1.02]). Interim median OS was 16.9 vs 13.5 mo in Arm A vs Arm C in UT pts (HR, 0.78 [95% CI: 0.54, 1.12]) and 15.8 vs 13.4 mo, respectively, in LT pts (HR, 0.87 [95% CI: 0.70, 1.08]). See table for additional efficacy results. Conclusions: Exploratorysubgroup analyses suggest activity of atezo + plt/gem in both UT and LT mUC, with outcomes in UT pts comparable to those seen in the LT and ITT populations. Clinical trial information: NCT02807636. [Table: see text]

Palbociclib (PAL) + cetuximab (CET) vs CET in patients (pts) with head and neck cancer: Asian subgroup analysis

Abstract Background The double-blind, randomized, phase 2 PALATINUS trial found a trend in prolongation of median overall survival (OS) with PAL+CET vs CET in CET-naive pts with platinum-resistant, HPV-unrelated HNSCC (median OS: 9.7 mo vs 7.8 mo, stratified by performance status [PS] hazard ratio [HR]=0.82, 95%CI: 0.54-1.25, P = 0.18). This subgroup analysis evaluated the efficacy and safety of PAL+CET in Asian pts enrolled in PALATINUS in Japan, Korea, and China. Methods Pts were treated with CET+PAL (arm A) or placebo (arm B) and stratified by PS and prior immunotherapy (IT). 120 pts were required for 1:1 randomization to have ≥80% power to detect an HR of 0.6 (corresponding to a median OS of 10 mo in arm A and 6 mo in arm B) using a 1-sided log-rank test at α = 0.10. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR; complete or partial response per RECIST v1.1), and adverse events (AEs). Results Of 125 pts randomized in PALATINUS, 28 were enrolled from Asian countries (arm A: 15; arm B: 13). PS and prior IT were balanced between groups. Unbalanced primary sites included hypopharynx (arm A: 9; arm B: 1) and oral cavity (arm A: 3; arm B: 7). Other pt characteristics were similar between the 2 arms. Median OS was 7.1 mo (95%CI: 3.1-8.8) in arm A and 7.0 mo (95%CI: 4.1-9.5) in arm B (stratified by PS: HR = 0.72, 95%CI: 0.3-1.8, P = 0.24). Median PFS was 3.2 mo in arm A and 3.0 mo in arm B (stratified by PS: HR = 1.22, 95%CI: 0.5-3.0, P = 0.3). ORR was 13.3% (95%CI: 1.7-40.5) in arm A and 15.4% (95%CI: 1.9-45.4) in arm B. Hematologic AEs were reported primarily in arm A. No difference in safety profile was shown in the Asian vs overall populations. Conclusions Although PAL+CET showed a trend toward prolongation of median OS vs CET in the overall PALATINUS population, no significant difference in OS or PFS was apparent with PAL+CET vs CET in the subgroup of Asian pts, possibly due to the limited cohort size. Pfizer (NCT02499120)