Pts In Arm Research Articles

NRG-GI007: Secondary endpoints of safety assessment and clinical complete response (cCR) of chemoradiation with endoscopically injected oncolytic virus OBP-301 in medically inoperable esophageal cancer.

435 Background: Definitive chemoradiation (CRT) is a standard-of-care for patients (Pts) with medically inoperable esophageal cancer (EC). The NRG/RTOG 0436 study of cisplatin/paclitaxel and RT (+/- cetuximab) as definitive therapy showed that 58% of control arm Pts have locally persistent disease. OBP-301 is a conditionally-restricted, replication-competent adenovirus derived from human adenovirus type 5 that adds a human Telomerase Reverse Transcriptase gene promoter, replicating only in tumor cells to cause lysis.It may cause immunogenic cell death, enhance RT increasing radiosensitization by blocking DNA repair and improve local control. Methods: In NRG-GI007, a phase 1 study (NCT04391049), OBP-301 was added to weekly carboplatin/paclitaxel and RT (50.4 Gy/28 fxs) for medically inoperable EC Pts with pathologically proven adenocarcinoma or squamous cell carcinoma (SCC) of the esophagus or Siewert Type I/II gastroesophageal junction. Pts receive 1-2mL of intratumoral OBP-301 1×10 12 virus particles/ml via endoscopy 3 days prior to and then at days 12 and 26 of CRT. The primary endpoint was protocol-defined dose-limiting toxicity, already reported. Secondary endpoints reported here are treatment-related (definitely or probably related to any protocol treatment) AEs - all and grade 4+ non-hematologic, and cCR in the primary tumor, defined as negative EGD/biopsy 6-8 weeks post-CRT. Per the protocol design, no statistical testing is done for these endpoints. Results: Initially, 6 evaluable (eligible and started protocol treatment) Pts were enrolled from June 2020 to April 2023. As initial dose level was deemed safe, an additional 9 Pts were enrolled from August 2023 to July 2024, totaling 15 evaluable Pts for secondary endpoints. Median age was 74 years, 9 Pts (60%) with ECOG PS 1. 11 Pts (73%) had adenocarcinoma and 4 had SCC; 11 Pts had N+ disease. 14 Pts (93%) received all planned OBP-301 injections and received 50.4 Gy RT. The most common treatment-related grade 3/4 AEs were decreased neutrophil (6 Pts; 40%) and lymphocyte counts (5 Pts; 33%), expected with CRT. No grade ≥3 OBP-301-related non-hematologic AEs were reported. 2 Pts died prior to restaging neitherdefinitely or probably related to OBP-301: 1 Pt developed grade 5 respiratory failure 6 weeks after CRT (suspected RT pneumonitis), while a 2 nd Pt had an unrecognized tumor invasion of the bronchus at baseline, which worsened during week 3 of CRT, resulting in a grade 5 tracheo-esophageal fistula. 2 Pts have not yet reached time for restaging. All 11 Pts who have been restaged had a cCR, for a preliminary cCR rate of 100% (95% CI: 74.1%, 100%). Conclusions: OBP-301 + CRT is safe and the preliminary cCR rate compares favorably to the historical control from NRG/RTOG 0436. Updated safety and cCR data will be presented. A randomized study is being planned. Clinical trial information: NCT04391049 .

Effect of chemotherapy/targeted therapy alone vs. chemotherapy/targeted therapy followed by radical surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction: The IKF-575/RENAISSANCE phase III trial.

LBA4001 Background: The IKF-575 trial investigates the long-standing question about the role of surgical intervention in limited-metastatic gastric / esophagogastric junction cancer after systemic induction therapy. Methods: Previously untreated patients (pts) with limited metastatic disease (retroperitoneal lymph node (RPLN) metastases only or a maximum of one incurable organ site that is potentially resectable or locally controllable with or without retroperitoneal lymph nodes) received 4 cycles of FLOT, + trastuzumab if Her2+ or + nivolumab if PD-L1 positive. Pts without progression after 4 cycles were randomized to receive additional FLOT (Arm B) or radical complete surgical resection of primary and metastases followed by the same treatment (Arm A). It was planned to randomize 176 pts for which 271 pts had to enrolled. The primary endpoint was overall survival in the ITT population using Kaplan-Meier estimates. Recruitment was stopped after enrollment of 183 patients (141 patients randomized) with minimal impact on statistical power, due to a slow enrollment rate. Results: The ITT comprised 139 pts (A, 67; B, 72): 20% had RPLN metastases only, 58% organ metastases only, and 22% had both. Surgery in Arm A (ITT) was performed in 91% of pts and R0-resection rate (primary) was 82%. 30-d and 90-d mortalities in the surgery population were 3% and 8%. At least 4 additional cycles of post-op or post-randomization chemotherapy were achieved in 42% of pts in Arm A vs. 71% of pts in Arm B. The primary endpoint ovrall survival was not met due to increased early mortality in the surgery Arm leading to crossing survival curves with OS 25%- and 75%-Quantiles being 10 vs. 14 months and 65 vs. 41 months for Arms A vs. B, respectively. Pts with RPLN metastases only seemed to benefit most from the surgical approach (mOS, 30 vs. 17 months; 5y OS 38% vs. 19%; still having increased early mortality), while pts showing no response to chemo (mOS, 13 vs. 22 months) or pts with peritoneal disease (mOS, 12 vs. 19 months) derived a detrimental effect. Conclusions: The IKF-575/RENAISSANCE trial is negative but informs future research. Future protocols should focus on pts with RPLN only disease and exclude non-responding pts or those with peritoneal disease. There is a need for strategies against the early mortality caused by chemotherapy interruption. Clinical trial information: NCT02578368 .

Combination of encorafenib and binimetinib followed by ipilimumab and nivolumab versus ipilimumab and nivolumab in patients with advanced BRAF-V600E/K-mutated melanoma: The primary analysis of an EORTC randomized phase II study (EBIN).

LBA9503 Background: The benefit of an induction treatment with targeted therapy (TT) with BRAF+MEK inhibitors prior to a combined immunotherapy (IT) with ipilimumab (ipi) + nivolumab (nivo) in patients (pts) with advanced BRAF-V600E/K mutant melanoma is still unclear. Methods: EBIN is an international randomized controlled phase II trial comparing upfront IT (arm A: nivo [3mg/kg] + ipi [1mg/kg] q3w x4 followed by nivo 480 mg q4w) with the sequential approach (arm B: 3 months induction with TT with encorafenib 450 mg QD + binimetinib 45 mg BID orally, followed by IT using the same regimen as in arm A), total treatment [Tx] duration in both arms: 2 years. In arm B, pts were allowed to be rechallenged with TT after progression. Pts with measurable BRAF-V600E/K unresectable stage III/IV melanoma, except pts with uveal melanoma, untreated or symptomatic brain or leptomeningeal involvement were randomly assigned 1:1 to arm A or B. Prior Tx for advanced melanoma was not allowed but adjuvant Tx completed at least 6 months before randomization was permitted. The primary objective was to show superiority of arm B in progression-free survival (PFS) using the log-rank test stratified by stage and lactate dehydrogenase (LDH) with a 1-sided alpha error set at 5%. The study had a power of 80% to detect a HR of 0.65. The study planned to randomize 135 pts in each arm. Results: All 136 pts randomized to arm B and 131 out of 135 in arm A started protocol Tx. At baseline, 170 (63%) pts had stage M1c, 129 (48%) had LDH above upper limit normal (ULN), 74 (27%) had a liver metastasis, and 19 (7%) received adjuvant therapy. The median follow-up was 21 months. In arm B, 135 (99%) pts were free of progression at week 12, when the end of TT was scheduled. In the intention-to-treat population, there was no evidence of a longer PFS in arm B (HR = 0.87, 90% confidence interval [CI] 0.67-1.12, p = 0.36). In a prespecified subgroup analysis, the HR for arm B vs arm A was 2.09 (95% CI 0.96-4.53), 0.74 (95% CI 0.43-1.29), 0.86 (95% CI 0.54-1.37), and 0.46 (95% CI 0.21-1.03) in pts with stage III with LDH≤ULN or M1a, M1b/M1c with LDH≤ULN, ULN < LDH≤2ULN, and LDH > 2ULN, respectively (p-value for interaction 0.045). In a post-hoc subgroup analysis, pts with ≥3 metastatic sites or a sum of target lesions ≥10cm at baseline did not have a longer PFS in arm B but in pts with liver metastasis the Tx HR was 0.48 (95% CI 0.28-0.80, p-value for interaction 0.008). The objective response rate was 53% in arm B and 45% in arm A. Complete response rate was 12% in arm B and 10% in arm A. Grade ≥3 adverse events occurred in 58% of pts in arm B and 51% in arm A. Conclusion: The EBIN trial shows there is no difference in PFS between the two treatment arms for unselected patients but supports the hypothesis that patients with very high LDH and those with liver metastases benefit from the sequential approach. Clinical trial information: NCT03235245 .

Phase 3 study (PIVOTAL) of neoadjuvant intralesional daromun vs. immediate surgery in fully resectable melanoma with regional skin and/or nodal metastases.

LBA9501 Background: PIVOTAL (NCT02938299) is an open label, randomized, multicenter, phase 3 trial evaluating Daromun as a neoadjuvant intralesional therapy for resectable, locally advanced Stage III melanoma. Daromun, a combination of two antibody-cytokine fusions (L19IL2 and L19TNF) showed efficacy in a phase 2 study (NCT02076633) in unresectable melanoma patients (pts). Methods: PIVOTAL was run at 22 sites in 4 EU countries. Pts were 1:1 randomly assigned to receive up to 4 weekly intratumoral injections of Daromun followed by surgery (week 5 to 8; treatment arm) or surgery alone within 4 weeks from randomization (control arm). Each weekly administration of Daromun (13 Mio IU of L19IL2 and 400 μg of L19TNF) was distributed among all injectable tumor lesions. Cutaneous melanoma pts with skin and/or LN metastases amenable to complete surgical resection were eligible. Prior anti-tumor treatments including surgery, radiation therapy (RT) and systemic therapies were allowed. Any approved adjuvant treatment post-surgery during follow-up was equally allowed. Pts with uveal or mucosal melanoma, metastatic melanoma with unknown primary, or distant metastases at screening (ruled out by PET/CT) were not eligible. Results: From 07/2016 to 08/2023, 127 pts were randomized to the treatment and 129 to the control arm. Most pts had received previous treatments, including surgery, systemic therapy or RT (Table). The study’s primary endpoint was relapse-free survival (RFS), assessed by investigators and confirmed by retrospective Blinded Independent Central Review (BICR) of PET/CT scans. The primary outcome analysis shows an HR between the RFS of the treatment and control arm of 0.59 [95% CI 0.41-0.86; log-rank p=0.005] as per BICR assessment and 0.61 [0.41-0.92; p=0.018] as per investigator assessment (power = 85%; two-sided α = 0.05). Median RFS was 16.7 mo. in the treatment and 6.9 mo. in the control arm as per BICR. Moreover, distant metastasis-free survival (DMFS) was significantly improved by the neoadjuvant treatment, with an HR of 0.60 [0.37-0.95; p=0.029]. Complete pathological responses (pCR) after surgery were recorded in 21% of treatment arm pts. The safety profile of Daromun was characterized mostly by low-grade, local adverse events (14% grade 3 TEAEs). Systemic AEs were limited and of low grade (no autoimmune TEAEs and no drug-related death recorded). Conclusions: The analysis of the primary efficacy endpoint RFS and of secondary endpoints DMFS, pCR and safety show that neoadjuvant Daromun is an effective and safe therapeutic option for resectable, locally advanced melanoma pts. Clinical trial information: NCT02938299 . [Table: see text]

Neoadjuvant treatment of IBI310 (anti-CTLA-4 antibody) plus sintilimab (anti-PD-1 antibody) in patients with microsatellite instability-high/mismatch repair-deficient colorectal cancer: Results from a randomized, open-labeled, phase Ib study.

3505 Background: Immune checkpoint inhibitors have been used in neoadjuvant setting and showed promising clinical benefits in various tumors. Herein, we evaluate IBI310 plus sintilimab as neoadjuvant treatment in patients (pts) with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) colorectal cancer (CRC) in a randomized, open-labeled, phase Ib study. Methods: Previously untreated pts with locally advanced (stage IIB-III), resectable, MSI-H/dMMR CRC were enrolled and randomized to receive 1 cycle of IBI310 1mg/kg plus 2 cycles of sintilimab 200 mg Q3W (arm A) or 2 cycles of sintilimab 200 mg Q3W (arm B) as neoadjuvant treatment. The stratification factors were risk evaluation at baseline (high risk: stage T4 or N2 vs low risk: stage T1-3 and N1) and age ( < 55 years vs ≥55 years). Curative resection was scheduled on day 36 to 56 after first dose of neoadjuvant treatment. Primary endpoint was pathological complete response (pCR) rate. Secondary endpoints included R0 resection rate and safety. Results: As of February 4, 2024, 101 pts were enrolled (males: 55.4%, median age: 56 years, ECOG PS 1: 54.5%, high risk: 76.2%) and randomized into arm A (n = 52) and arm B (n = 49). In arm A, 1 pt had early termination of treatment (withdrawal). In arm B, 4 pts had early termination of treatment (1 withdrawal, 1 died, 2 continued neoadjuvant sintilimab). Scheduled curative resection were performed in 51 (98.1%) pts in arm A and 45 (91.8%) pts in arm B. Postoperative evaluation revealed mismatch repair-proficient (pMMR) in 1 pt each in arm A and arm B. The pCR rates were 80.0% (40/50, 95%CI: 66.3-90.0) in arm A vs 47.7% (21/44, 95%CI: 32.5-63.3) in arm B (p = 0.0007). All pts received surgery had R0 resection. Median time between first dose of neoadjuvant treatment and surgery was 47 days (range: 35-82). Surgery delay occurred in 3 pts including 2 pts in arm A due to grade 2 hypothyroidism (2 days delay) and grade 1 hyperthyroidism (13 days delay), and 1 pt in arm B for other reason (26 days delay). Treatment-emergent adverse events (TEAEs) occurred in 46 pts (88.5%, grade≥3 in 13 pts) in arm A and 39 pts (79.6%, grade≥3 in 9 pts) in arm B. Immune-related adverse events (irAEs) occurred in 22 pts (42.3%) in arm A and 18 pts (36.7%) in arm B. Grade ≥3 irAEs occurred in 3 pts in arm A, including immune-mediated myocarditis, ileus and enteritis, and in 4 pts in arm B, including alanine aminotransferase increased, rash, hypothyroidism and myocarditis. Serious TRAEs occurred in 4 (7.7%) pts in arm A and 3 (6.1%) pts in arm B. TRAE leading to death occurred in 1 pt in arm B (myocarditis). Conclusions: Neoadjuvant IBI310 plus sintilimab significantly improved pCR rate than sintilimab alone in MSI-H/dMMR CRC. The safety profiles were comparable and manageable in both treatment arms. Clinical trial information: NCT05890742 .

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]

Two stage, multi-center trial of cadonilimab and LM-302 for patients with CLDN18.2+ biliary tract cancer (BTC) that failed chemotherapy and PD-(L)1 antibody (ZSAB-Calm).

e16152 Background: BTC is a lethal disease with limited effective treatments, especially for those who have failed immune checkpoint inhibitors (ICIs) plus chemotherapy. Cadonilimab, a tetrameric bispecific antibody targeting PD-1 and CTLA-4, showed promising safety profile and efficacy in several malignant tumors. LM-302 is a novel antibody-drug conjugate targeting CLDN18.2, a tight junction protein expressed on the cell surface of many solid tumors, including BTC. Here, we present preliminary data on the safety and efficacy of cadonilimab plus LM-302 in CLDN18.2+ BTC patients (pts) with prior treatment of ICI and chemotherapy. Methods: This ongoing study is a multicenter, two-stage, randomized phase Ib/II clinical trial. In the dose-escalation phase, 6 pts (no requirement for CLDN18.2) are enrolled, using "3+3" design to determine the RP2D. Pts will receive LM302 (1.6mg/kg or 1.8mg/kg Q2W) and cadonilimab (6mg/kg Q2W). The expansion stage is expected to enroll 90 pts (CLDN18.2 + staining in ≥40% of tumor cells), randomized into 3 arms with 30 patients each. Arm 1: cadonilimab (6mg/kg Q2W), Arm 2: LM-302 (1.8mg/kg, Q2W), Arm 3: cadonilimab (6mg/kg Q2W) and LM-302 (RP2D). The primary endpoints are the safety (CTCAE 5.0) in phase 1b and ORR (RECIST1.1) in phase 2. The secondary endpoints include DCR, PFS, OS and safety. Results: A total of 18 pts were enrolled from Aug 4, 2023 to Jan 15, 2024. Median age was 62 (range: 42-79), 44% were male. 61% have intrahepatic cholangiocarcinoma. 78% pts with distant metastasis were diagnosed as stage IV. In the dose-escalation phase, 7 pts were enrolled. The first pt was discontinued after only one dose due to percutaneous transhepatic cholangiography and drainage catheter infection and gastrointestinal bleeding (unrelated to treatment). No DLTs were observed. 7 (100%) pts experienced TRAEs. The most common TRAEs were bilirubin increase (71.4%) thrombocytopenia (57.1%), neutropenia (57.1%), infusion reactions (rash) (42.9%), leukopenia (42.9%), anemia (28.6%). Only 2 pts had grade 3 TRAEs including anemia(1pt), neutropenia, leukopenia and rash (1pt). There was no grade≥4 TRAE. Of the 6 efficacy-evaluable pts, 3 pts(CLDN18.2 expression in 30%, 40%, 80%)achieved PR resulting in a BOR of 50% in Phase Ib. The RP2D for LM-302 was 1.8mg/kg. In expansion phase, 11 pts with CLDN18.2+ BTC were randomly enrolled. The median number of treatment cycles was 2 (range 1-8), with 4 pts each in Arm 1 and Arm 2, and 3 pts in Arm 3. Among the 11 pts, 5 (45.5%) occurred TRAEs, with 3 pts in Arm 3 and 2 pts in Arm 1. The most common TRAEs were neutropenia (18.2%), neutropenia (18.2%). Only 1 pt in Arm 3 experienced grade 3 neutropenia. One pt had a SAE of myocardial infarction (unrelated to treatment). Conclusions: Cadonilimab combined with LM-302 has manageable safety and promising antitumor activity in CLDN18.2+ BTC. Clinical trial information: NCT05994001 .

Phase 3 study of disitamab vedotin with pembrolizumab vs chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma that expresses HER2 (DV-001).

TPS4616 Background: Platinum-based chemotherapy (chemo) has been the standard first-line (1L) therapy for locally advanced or metastatic urothelial carcinoma (la/mUC). Recently, enfortumab vedotin, a nectin-4-directed antibody-drug conjugate (ADC) with a monomethyl auristatin E (MMAE) payload, plus pembrolizumab (pembro) showed improved survival over chemo. Human epidermal growth factor receptor 2 (HER2) expression (immunohistochemistry [IHC] 1+-3+) has been reported in approximately half of all patients (pts) across tumor types, including UC, and is a biomarker that may be associated with poor outcomes. Disitamab vedotin (DV; RC48-ADC) is an investigational ADC comprising a fully humanized HER2-directed monoclonal antibody, disitamab, conjugated to MMAE via a protease-cleavable mc-vc linker. DV elicits antitumor activity through multimodal mechanisms of action, including MMAE-mediated direct cytotoxicity, bystander effect, and immunogenic cell death. DV has shown encouraging activity with a manageable safety profile in pts with la/mUC—as a single agent in a HER2-expressing post-platinum setting (IHC 3+/2+; ORR, 50.5%; median [m]PFS, 5.9 months; mOS, 14.2 months) and in combination with a programmed cell death protein 1 (PD-1) inhibitor in all comers (ORR, 76.0% in treatment-naive pts; 83.3%, 64.3%, and 33.3% in HER2 IHC 3+/2+, IHC 1+, and IHC 0 subgroups, respectively). Improved outcomes observed with an MMAE payload plus PD-1 inhibition across the ADC landscape, along with DV data, provide a robust rationale for this phase 3 trial of DV with pembro in the 1L setting for HER2-expressing la/mUC. Methods: DV-001 (NCT05911295) is an open-label, randomized, multicenter, controlled phase 3 trial evaluating DV with pembro vs chemo in pts with previously untreated HER2-expressing la/mUC. Pts will be randomized 1:1 to Arm A or B. Pts in Arm A will receive DV IV every 2 weeks and pembro IV every 6 weeks. Treatment will continue until disease progression or intolerable toxicity; pembro will be administered for a maximum of 18 6-weekly infusions (approximately 2 years). Pts in Arm B will receive platinum-based chemo with gemcitabine IV on Days 1 and 8 of every 3-week cycle, and either cisplatin or carboplatin on Day 1 of every 3-week cycle for 4-6 cycles. Maintenance therapy with avelumab after completion of chemo may be given to eligible pts where approved and available. Pts must have previously untreated la/mUC, measurable disease per RECIST v1.1, ECOG PS of 0-2 and must be eligible for platinum-based chemo. HER2 expression must be determined using the VENTANA 4B5 HER2 IHC Assay centrally and using the most recent archival or fresh tumor sample. Primary endpoints include PFS per blinded independent central review and OS. Enrollment is ongoing in the US, Canada, and Australia and is planned globally. Clinical trial information: NCT05911295 .

First-in-human phase I trial of the oral first-in-class ubiquitin specific peptidase 1 (USP1) inhibitor KSQ-4279 (KSQi), given as single agent (SA) and in combination with olaparib (OLA) or carboplatin (CARBO) in patients (pts) with advanced solid tumors, enriched for deleterious homologous recombination repair (HRR) mutations.

3005 Background: USP1 is a deubiquitinase that regulates DNA damage response pathways, such as Translesion Synthesis and Fanconi Anemia pathways. KSQi is a potent, selective small molecule inhibitor of USP1 with anti-proliferative activity in tumors with HRR mutations. The combination of KSQi and PARP inhibitors (PARPi) showed strong synergy in Ovarian and TNBC PDX models, supporting this clinical trial. Methods: This is a 2-part study: Part 1 dose escalation using a BOIN design explored safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity of KSQi as SA (Arm 1) and in combination with OLA at 200 mg BID (Arm 2) or CARBO at AUC 4 (Arm 3) to determine the MTD and/or recommended dose for expansion (RDE). Part 2 will assess efficacy and safety of the combinations in expansion cohorts. Results: As of Jan 4, 2024, 64 pts (19m/45f; median age 63 y) received KSQi 100 - 1250 mg; Arm 1: 100 mg (3 pts), 150 (3), 200 (4), 300 (6), 450 (5), 650 (9), 900 (7) and 1250 (5); Arm 2: 200 (5), 450 (5) and 900 (5); Arm 3: 200 (3) and 450 (4). Median number of prior therapies was 5, 4 and 3 for Arm 1, 2 and 3, respectively. 29% had prior PARPi in Arm 1, 53% in Arm 2, and 71% in Arm 3. All pts in Arms 2 and 3 had tumors with deleterious HRR mutations. Most common treatment-emergent adverse events (TEAE) were anemia (36%), increased creatinine (33%) as SA, and anemia in combination with OLA (87%) and CARBO (71%). The most common G3+ TEAEs were hyponatremia (12%) as SA and anemia in combination with OLA (73%) and CARBO (29%). DLTs (n = 3) were G3 maculopapular rash at 1250 mg (Arm 1) and G3 WBC decrease at 200 mg, G3 anemia at 450 mg (Arm 2). 30% (19/64) of pts had an interruption in KSQi dosing and 1 (1.6%) discontinued treatment. PK AUC and Cmax increased almost dose-proportionally up to 650 mg. A preliminary review of OLA concentrations following co-administration with KSQi showed no significant impact of OLA at C2D1. Ubiquitinated PCNA induction was observed in paired tumor biopsies from pts receiving KSQi, supporting intra-tumoral USP1 inhibition. A RECIST PR was observed in a fallopian tube cancer pt lasting 7 weeks and SD in 9 pts treated with SA KSQi; best response in combination with OLA was SD in 6 pts and 2 SD with CARBO. Disease control rate at 16 weeks was 28% (Arm 1), 40% (Arm 2) and 29% (Arm 3). Conclusions: KSQi is a first-in-class USP1 inhibitor with an acceptable safety profile as SA and in combination. An MTD was not reached in any Arms. PD results support the mechanism of action of USP1 inhibition. The RDE will be determined in additional back-fill cohorts. Clinical trial information: NCT05240898 .

Phase 3 study results of isatuximab, bortezomib, lenalidomide, and dexamethasone (Isa-VRd) versus VRd for transplant-ineligible patients with newly diagnosed multiple myeloma (IMROZ).

7500 Background: The first line of treatment (tx) is important for patients (pts) with newly diagnosed multiple myeloma (NDMM) as pts may not have a chance for subsequent therapy. VRd is currently a standard of care (SOC) in NDMM. Isa is an approved anti-CD38 monoclonal antibody (mAb) inducing myeloma cell death through multiple mechanisms. In the Phase 3 IMROZ study (NCT03319667), we investigate the efficacy and safety of Isa-VRd vs VRd in transplant-ineligible NDMM pts. Methods: IMROZ is a global, prospective, randomized, open-label study done at 102 study sites in 21 countries. Included pts had active, measurable NDMM not considered for transplant due to elderly age or comorbidities. Pts aged ≥80 were excluded. Pts were randomized 3:2 and stratified by age, R-ISS stage and China vs non-China, to receive Isa-VRd or VRd. Isa-VRd arm pts received Isa (10 mg/kg IV); both arms received V (1.3 mg/m2 SC), R (25 mg PO) and d (20 mg IV/PO). The primary endpoint was progression-free survival (PFS). Key secondary endpoints were complete response (CR), minimal residual disease negativity (MRD-) (10-5 by NGS) in pts with CR, very good partial response or better and overall survival. Adverse events (AEs) and laboratory parameters were graded with NCI CTCAE v4.03. Results: 446 pts (265 Isa-VRd, 181 VRd) were randomized; pt characteristics were well balanced. At data cutoff (26 Sep 2023), 125 (47.2%) and 44 (24.3%) pts in Isa-VRd and VRd arms were still on tx, respectively. Median (mdn) tx duration was 53.2 (Isa-VRd) vs 31.3 (VRd) mo; addition of Isa did not significantly affect relative dose intensity of VRd. At mdn follow-up of 59.7 mo, mdn PFS was not reached (Isa-VRd) vs 54.3 mo (VRd); HR 0.596 (98.5% CI 0.406–0.876), log-rank p=0.0005. From the current trend, projected Isa-VRd mdn PFS will reach ~90 mo. PFS benefit was consistent across subgroups and maintained through subsequent line of therapy (PFS2 HR 0.697; 95% CI: 0.51-0.952). Isa-VRd led to deep and sustained responses and was well-tolerated (Table). Exposure-adjusted Grade 5 TEAE rate was 0.03 (Isa-VRd) vs 0.02 (VRd). Conclusions: IMROZ is the first Phase 3 study of an anti-CD38 mAb with SOC VRd in this pt population to show a significantly reduced risk of progression or death by 40.4% vs VRd while providing deep and sustained responses. The safety profile was consistent with addition of Isa to VRd. Numerical differences in TEAEs are largely explained by longer exposure in the Isa-VRd arm. These results support Isa-VRd as a potential new SOC in pts not intended for transplant. Clinical trial information: NCT03319667 . [Table: see text]

Abstract PO4-25-04: MHC Class I and II Expression, Functional Tertiary Lymphoid Structure (TLS), and Outcomes in Early-Stage HER2-Positive (HER2+) Breast Cancer in NCCTG N9831 (Alliance)

Abstract Background: Tertiary lymphoid structure (TLS) is an organized form of ectopic lymphoid aggregates (LA) with secondary lymphoid organ structure. Several studies showed that the presence of TLS associates with improved outcomes in multiple cancers when treated with immune checkpoint inhibitors. However, data is currently limited regarding TLS and outcomes in HER2+ breast cancer patients (pts) treated with adjuvant trastuzumab. Furthermore, distinguishing TLS and simple LA is challenging in standard hematoxylin and eosin (H&E) staining, particularly when the germinal center is absent. Emerging studies also showed the prognostic value of MHC expression in breast cancer but mainly in triple-negative breast cancer. In this study, we evaluated integrated pathological quantification and genomic data to assess functional TLS in association with MHC expression and outcomes in the N9831 trial. Methods: Pathological evaluation of LA in H&E slides from pts treated in Arm A (chemotherapy alone) and Arm C (chemotherapy with concurrent trastuzumab) in N9831 was performed. NanoString was used to quantify mRNA of MHC class I and II expression as well as TLS-related immune genes, including IFNG, ICOSLG, CXCL13, CXCR3, BCL6, IL21R, ICOS, PDCD1, CXCR5, CXCL9, TBX21, CD38, CXCL10, CLXCL11, IL21, CD200, CD19, MS4S1. Wilcoxon rank sum test, Chi-squared test, Kaplan-Meier method, and Cox regression model were used to evaluate the association between LA and baseline characteristics, MHC expression, and outcomes. Results: LA was evaluated in 526 pts in Arm A and 485 in Arm C. Greater number of LA was significantly associated with stromal tumor-infiltrating lymphocytes (sTILs), hormone receptor negative, and higher tumor grade, but not stage and age. Using multivariable Cox regression analysis, increasing numbers of LA were associated with improved recurrence-free survival in both arms combined (RFS, p 0.028). However, when evaluating each arm separately, LA was associated with improved RFS only in Arm A (HR 0.6, 95%CI 0.43-0.84, p 0.003) but not in Arm C (HR 0.72, 95%CI 0.47-1.1, p 0.134). We further evaluated TLS-related immune genes in 252 pts in Arm C with LA ≥ 1. As a continuous variable, higher expression of BCL6 (HR 0.61, 95%CI 0.41-0.92, p 0.019) and IL21R (HR 0.78, 95%CI 0.62-0.98, p 0.03) were associated with improved RFS in Arm C pts with LA ≥ 1. However, these genes were not significantly associated with outcomes in Arm C pts without LA with BCL6 (HR1.07, 95%CI 0.67-1.71, p 0.776) and IL21R (HR 0.96, 95%CI 0.71-1.29, p 0.775). Moreover, we evaluated differential gene expression between tumors with LA ≥ 1 with high BCL6 vs. LA 0. All MHC class I and II (HLA A, B, C, E, DQ, DM, DO, DP, and DQ) were significantly higher in tumors with LA ≥ 1 with high BCL6 (p < 0.001). Conclusion: A greater number of LA was associated with improved outcomes in pts with early-stage HER2+ breast cancer, particularly when treated with chemotherapy alone. Using histologic and genomic integration with the combination of pathological LA and TLS-related immune genes, we identified that pts with functional TLS with LA ≥ 1 and higher expression of BCL6 or IL21R had significantly improved outcomes when treated with trastuzumab. High MHC class I and II expressions are associated with the presence of functional TLS, underscoring the crucial role of antigen presentation in the generation of an effective adaptive immune response. Support: U10 CA180821, U10 CA180882, U24 CA196171, https://acknowledgments.alliancefound.org; Genentech; Clinicaltrials.gov Id: NCT00005970 Citation Format: Saranya Chumsri, Tracy Shachner, Zhuo Li, Nadine Norton, Alvaro Moreno-Aspitia, Gerardo Colon-Otero, Edith Perez, Aziza Nassar, E. Thompson, Keith Knutson. MHC Class I and II Expression, Functional Tertiary Lymphoid Structure (TLS), and Outcomes in Early-Stage HER2-Positive (HER2+) Breast Cancer in NCCTG N9831 (Alliance) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-25-04.

Abstract LBO1-02: Pathologic complete response (pCR) of neoadjuvant therapy with or without atezolizumab in HER2-positive, early high-risk and locally advanced breast cancer: APTneo Michelangelo randomized trial

Abstract Background: Neoadjuvant dual targeting of HER2 with trastuzumab (H) and pertuzumab (P) plus chemotherapy is the standard of care for high-risk HER2-positive (HER2+) breast cancer (BC). Compelling data show the contribution of the immune system in prognosis and response/resistance to HER2 directed therapies, supporting combination of immune checkpoint inhibitors with anti HER2 antibodies. We designed APTneo to test the role of adding atezolizumab to neoadjuvant dual targeting of HER2 with chemotherapy, and the value of also using anthracyclines in this setting. Methods: In this multicenter open label phase III trial (NCT03595592), 661 patients (pts) with high-risk early and locally advanced (LA) centrally confirmed HER2+ BC were randomized to neoadjuvant HPCT (H and P d1, carboplatin and paclitaxel iv d1 and 8) given q3 wks for 6 cycles w/o (n=223, ARM A) or with atezolizumab 1200 mg iv d1 (n=438, ARM B). In Arm B pts were randomized to Arm B1 (n=218) to receive anthracycline and cyclophosphamide (AC) + atezolizumab iv d1 q3 wks for 3 cycles followed by HPCT + atezolizumab for 3 cycles, or to arm B2 (n=220) to receive HPCT + atezolizumab for 6 cycles. After surgery pts continued adjuvant HER2 directed therapies w/wo atezolizumab until completion of 1 year. Among intent-to-treat (ITT) pts, 44.8% were LABC, 35% hormonal receptor (HR) negative and 30.4% PD-L1 positive. Primary endpoint is event-free survival (EFS) of Arm B vs A. A key secondary endpoint is the rate of pCR (ypT0/Tis, ypN0) w/wo atezolizumab. Primary population for all efficacy endpoints is ITT. We also assessed baseline PD-L1 status (Ventana SP142) and stromal Tumor Infiltrating Lymphocytes (sTILs). Results: pCR rate in Arm B (57.8%) vs Arm A (52.0%) was not significantly increased (adjHR 1.33, 95% CI 0.95-1.86; p=0.091). Also, the difference in pCR rate in Arm B1 (61.9%) vs Arm B2 (53.6%) was not significant (adjHR 1.402, 95% CI 0.95-2.07; p=0.089). Compared to Arm A, Arm B1 had a 9.9% significantly higher pCR rate (multivariate analysis in Table). The different pCR rate in arms B1 and A was similar regardless of HR and PD-L1 status. High sTILs (≥30%) and PD-L1positive tumors had a higher likelihood of pCR in all arms. Serious adverse events (SAE) after start of therapy occurred in 6.8% pts in Arm A and 14.1% in Arm B (p=0.0064). SAE were numerically more frequent in Arm B1 than Arm B2 (16.7% and 11.6%, respectively), due to hematological toxicity with AC. Immune-related SAE were quite infrequent and similar in B1 (4.7%) and B2 (7.8%), respectively. No grade 5 AE did occur. Conclusions: Addition of atezolizumab to chemotherapy and HP did not significantly increase the rate of pCR in women with HER2+ BC. An exploratory analysis showed that adding atezolizumab to neoadjuvant AC followed by HPCT led to higher pCR rate compared to HPCT and atezolizumab. This could be because of anthracyclines themselves or to drug-drug enhancement of anthracyclines and immune modulation. Atezolizumab did not cause major tolerability issues. Molecular studies of collected biospecimens are ongoing. Patients will continue to be followed up for EFS and overall survival analyses. Table. Supported in part by unrestricted grant from Hoffman-La Roche, Ltd, Switzerland Citation Format: Luca Gianni, Elisabetta Munzone, Mauro Mansutti, Giampaolo Bianchini, Yann Izarzuzaga, Elena Rota Caremoli, Luc Dirix, Lucia Del Mastro, Santiago González-Santiago, Andreas Schneeweiss, Jose Ponce, Chiun-Shen Huang, Pauline Wimberger, Sevilay Altintas, Miguel Martín, Nicoleta Antone, Christian F. Singer, Ugo De Giorgi, Ana Godoy Ortiz, Hans-Joachim Lueck, Riccardo Spezia, Angelica Fasolo, Giuseppe Viale, Pinuccia Valagussa. Pathologic complete response (pCR) of neoadjuvant therapy with or without atezolizumab in HER2-positive, early high-risk and locally advanced breast cancer: APTneo Michelangelo randomized trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr LBO1-02.

Abstract PS16-01: Comparison of an Atezolizumab monotherapy window followed by Atezolizumab and chemotherapy vs. Atezolizumab and chemotherapy alone in triple negative breast cancer (TNBC) – final analysis of the neoadjuvant neoMono trial

Abstract Background: Improvement of systemic therapy of TNBC still is a medical need. Exploratory data from the neoadjuvant GeparNuevo trial suggested a benefit from an immune checkpoint inhibitor (ICI) monotherapy window in TNBC. The neoMono trial prospectively analyzed whether the addition of a preceding Atezolizumab monotherapy window prior to Atezolizumab and chemotherapy (CTX) improves pCR rates among patients (pts) with early TNBC. In an interim analysis after 100 pCR events, patients with unselected TNBC did not show a significant benefit from an Atezolizumab monotherapy window, while an exploratory analysis suggested a highly clinically relevant benefit among pts with PD-L1 positive TNBC. Here we present the final primary endpoint analysis. Methods: NeoMono is a phase 2 randomized multicenter trial that was planned to recruit a maximum of 458 female and male pts with primary TNBC (defined as ER/PR < 10% and HER2 negative) with tumor stages cT1c – cT4d (cN0 and cN+). As the protocol mandated termination of trial recruitment based on the results of the interim analysis, the final ITT population was limited to 359 pts. PD-L1 status had to be identifiable by central pathology by means of the VENTANA PD-L1 (SP142) assay and was defined by PD-L1 expression on immune cells (IC). Neoadjuvant treatment in both study arms consisted of Atezolizumab 1200 mg every 3 weeks in addition to neoadjuvant CTX (12 x Carboplatin/Paclitaxel q1w followed by 4x Epirubicin/Cyclophosphamide q3w). Combination therapy in arm A was preceded by an Atezolizumab monotherapy window of 840 mg once two weeks prior to initiation of combination therapy, while patients in arm B received no immune monotherapy window. Study goals are to compare the efficacy of neoadjuvant CTX + Atezolizumab with versus without a two-week atezolizumab monotherapy window preceding CTX + ICI (primary endpoint: pCR) and to identify biomarkers for response and resistance through analysis of sequential tissue and liquid biopsies. The neoMono statistical design uses Bayesian posterior probabilities (uniform prior distribution) and logistic regression to analyze the primary endpoint. Results: 180 pts in arm A and 179 in arm B from 34 study sites were included in the final primary endpoint analysis. Demographics and baseline characteristics as well as drug exposure were well-balanced in both arms. Posterior mean pCR rates in the ITT population in study arms A and B were 65.7% (95% high posterior density interval (HPDI): 58.5%, 72.5%) and 69% (62.2%, 75.9%), respectively. In an exploratory analysis stratified by PD-L1 IC status (negative: < 1% versus positive: ≥ 1%), pCR rates in arm A were 91.5% in the PD-L1 IC-positive group and 56.1% in the PD-L1 IC-negative group, the corresponding pCR rates in arm B were 82.2% and 64.5%, respectively. In a multivariate analysis of the ITT population including tumor size, nodal status, tumor grade, age and PD-L1 status, the odds ratio for achieving a pCR was 4.77 (p < 0.001) for PD-L1-positive and 2.36 (p=0.023) for grade 3 tumors. In an exploratory analysis including HER2 status, odds for achieving a pCR were significantly higher for patients with HER2-negative (IHC 0) vs. HER2-low tumors (OR 1.73, p=0.036). No new safety signals were observed. Conclusion: The final primary endpoint analysis of the neoMono trial demonstrated the highest pCR rates ever reported in a phase II/III trial in TNBC. While a significant impact of an ICI monotherapy window on the pCR rate after combination of CTX + ICI in an unselected ITT population could not be demonstrated, neoMono indicates for the first time in a randomized prospective setting that patients with immune active TNBC might derive particular benefit from a preceding ICI monotherapy window. The results of the neoMono trial are mainly justifying the conduction of a confirmative trial in immune active TNBC. However, our results underscore the potential role of pre-therapeutic ICI monotherapy window as part of future therapeutic concepts in TNBC. Citation Format: Hans-Christian Kolberg, Johannes Schumacher, Ramona Erber, Michael Braun, Peter A. Fasching, Eva-Maria Grischke, Christian Schem, Michael P. Lux, Mustafa Deryal, Oliver Hoffmann, Bernhard Heinrich, Georg Kunz, Kristina Lübbe, Petra Krabisch, Arndt Hartmann, Philip Raeth, Sabine Kasimir-Bauer, Cornelia Kolberg-Liedtke. Comparison of an Atezolizumab monotherapy window followed by Atezolizumab and chemotherapy vs. Atezolizumab and chemotherapy alone in triple negative breast cancer (TNBC) – final analysis of the neoadjuvant neoMono trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS16-01.

Abstract CT212: Phase Ib/II, global, open-label, randomized evaluation of atezolizumab (atezo) + etrumadenant (etruma) + chemotherapy (chemo) vs chemo alone in MORPHEUS-PDAC

Abstract Background: Adenosine signaling can suppress the immune microenvironment and promote tumor immunity in many cancers, including pancreatic ductal adenocarcinoma (PDAC). Etruma, a dual adenosine A2a/A2b receptor antagonist, was evaluated in combination with atezo (anti-programmed death-ligand 1 [PD-L1] antibody) and chemo vs chemo alone (control) in patients (pts) with first-line PDAC in the MORPHEUS-PDAC study (NCT03193190). Methods: Pts were randomized to receive atezo (840 mg IV; Days 1 and 15 of 28-day cycles) + etruma (150 mg orally once daily) + chemo (nab-paclitaxel 125 mg/m2 IV and gemcitabine 1000 mg/m2 IV; Days 1, 8 and 15 of 28-day cycles), or chemo alone, until unacceptable toxicity or loss of clinical benefit. The primary efficacy endpoint was ORR. Key secondary endpoints were PFS, OS, DOR and DCR. Long-term safety results and exploratory biomarkers were examined. Results: Sixteen pts were randomized to atezo + etruma + chemo (15 treated) and 21 to chemo (20 treated). Baseline demographics were generally similar between arms. At 108 weeks, confirmed ORR was 26.7% (n=4) for atezo + etruma + chemo and 45.0% (n=9) for chemo alone. Median PFS was 8.21 vs 6.80 mo, and median OS was 16.49 vs 12.12 mo with atezo + etruma + chemo vs chemo, respectively (Table). While based on limited data, there were no clear associations between baseline levels of CD73 or PD-L1 and clinical outcomes. All treated pts had ≥1 treatment-related adverse event (TRAE); 3 pts in each arm withdrew from any treatment due to a TRAE, and 2 pts in the chemo arm had Grade 5 AEs. Conclusion: In MORPHEUS-PDAC, the ORR primary endpoint was not met although both median PFS and OS were numerically improved with the combination therapy, suggesting that the addition of etruma and atezo may confer a benefit. Overall, atezo + etruma + chemo was tolerable. Safety of the combination was consistent with the known risks of the individual treatments. TABLE 1. NAND Efficacy Atezo + etruma + chemo (n=15) Chemo (control) (n=20) Confirmed ORR (investigator-assessed RECIST 1.1), n (%)a 4 (26.7) 9 (45.0) 95% CI 7.8, 55.1 23.1, 68.5 DCR, n (%) 10 (66.7) 16 (80.0) 95% CI 38.4, 88.2 56.3, 94.3 Median PFS (investigator-assessed RECIST 1.1), mo 8.2 6.8 95% CI 5.9, 11.1 5.7, 9.9 HR (95% CI) 0.48 (0.2, 1.1) DOR, mo 4.9 5.4 95% CI 2.9, NE 2.8, 8.2 HR (95% CI) 1.43 (0.4, 5.3) Median OS, mo 16.5 12.1 95% CI 9.6, 19.7 10.0, 15.4 HR (95% CI) 0.67 (0.3, 1.5) Median survival follow-up, mo 16.5 11.4 NE, not evaluable. a One unconfirmed responder in the atezo + etruma + chemo arm; 2 unconfirmed responders in the chemo arm. Citation Format: Kyu-Pyo Kim, Mariano Ponz Sarvise, Teresa Macarulla, Angela Alistar, Eileen O'Reilly, Mathew Boakye, Hen Prizant, Trista Xu, Fiona Young, Janet Lau, Do-Youn Oh, Jill Lacy. Phase Ib/II, global, open-label, randomized evaluation of atezolizumab (atezo) + etrumadenant (etruma) + chemotherapy (chemo) vs chemo alone in MORPHEUS-PDAC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT212.

Abstract CT223: Dormancy reprograming therapy of 5-azacitidine (AZA) and all-trans retinoic acid (ATRA) in biochemically recurrent prostate cancer

Abstract Microenvironmental signals and epigenetic changes can instruct proliferative disseminated tumor cells to enter dormancy. The combination of Azacitidine (AZA) and All-trans retinoid acid (ATRA) can reprogram active prostate cancer (PCa) cells into a dormant state. Herein, we evaluated the safety and clinical activity of AZA + ATRA in patients (pts) with biochemically recurrent PCa. Eligible pts were those with diagnosis of PCa post-local therapy with rising PSA (PSADT < 10 mo). Pts were excluded if they had radiographic evidence of disease or if they were a candidate for salvage radiation therapy (RT). Eligible pts were randomized 1:1 to arm A vs. B. All pts received Lupron 7.5 mg IM at the start of study. Four weeks later, pts entered a 24-week treatment (tx) phase. Pts in arm A received AZA 40 mg/m2 SQ x 5 days and ATRA 45 mg/m2 PO x 5 days Q4W for 12 weeks (w), followed by 12w of observation. Pts in arm B underwent 12w of observation, followed by 12w of AZA and ATRA at same dosing as arm A. All pts underwent follow up until initiation of next tx. The primary endpoint was safety and tolerability as assessed by CTCAE v5.0. Key secondary endpoints included % of pts with prolongation of PSADT pre- and post-tx and time to next treatment (TTNT). Levels of dormancy biomarkers, BMP4 and BMP7, were quantified using ELISA. Circulating tumor cells (CTCs) were analyzed for positive expression of NR2F1 using immunofluorescence. Wilcoxon signed rank test was used for comparing the PSADT. All statistical analysis was performed in R. Fourteen pts were enrolled (A: N=6, B: N=8) with a median age of 66 (range 54-77). At baseline, mean PSA was 4.75 ng/ml (A: 7.11, B: 2.99) and mean PSADT was 2.89 months (A: 3.51, B: 2.43). Eight (57.1%) pts had a Gleason score > 8 at initial diagnosis (A: 83.3%, B: 37.5%). There were no reported Grade > 3 treatment-related adverse events (TRAEs) and no treatment discontinuations. The most common TRAEs included hot flashes, white blood cell decreased and lymphocyte count decreased (all 8.3% each), and anemia (5.6%). There was prolongation of PSADT pre- and post-tx in 6 (46%) pts, however, overall difference in PSADT was non-significant [p>0.1]. 13 out of 14 (93%) pts had TTNT of > 6 months. One pt developed radiographic progression prior to completion of tx phase and a total of 6 pts (42.8%) within 3 months of tx phase. Out of 8 pts, 37.5% and 75% of pts showed increased levels of BMP4 and BMP7 respectively. Upon tx, CTC count decreased in 3 out of 5 pts analyzed, while CTCs were undetectable in two pts. Upon tx, NR2F1 expression could not be detected due to non-detection of CTCs, except for one pt who showed 100% NR2F1 positive CTCs in follow up. AZA + ATRA appears safe and well tolerated, and there was clinical activity in a small subset of pts potentially correlated with dormancy. Additional prospective clinical studies are needed to elucidate dormancy mechanisms further and optimize dosing strategy. Citation Format: Vaibhav G. Patel, Deepak Singh, Himanshu Joshi, Bobby Liaw, Che-Kai Tsao, Matthew Galsky, Lindsay Diamond, Julio Agguire-Ghiso, William Oh. Dormancy reprograming therapy of 5-azacitidine (AZA) and all-trans retinoic acid (ATRA) in biochemically recurrent prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT223.

Abstract CT253: Results from KEYNOTE-B99: Phase 2 study of first-line (1L) pembrolizumab (pembro) plus investigational agents and chemotherapy (chemo) for extensive-stage small-cell lung cancer (ES-SCLC)

Abstract Background: ES-SCLC is an aggressive cancer with substantial mortality. Current 1L treatments include anti-PD-(L)1 + etoposide-platinum chemo (EP), but with minimal improvements in OS vs chemo. In the phase 3 KEYNOTE-604 study, pembro + EP significantly improved PFS (P = 0.0023) but not OS vs placebo + EP; ORR was also improved (71% vs 62%). We present data from the phase 2 KEYNOTE-B99 study (NCT04924101) of 1L pembro + investigational agents (MK-4830, anti-ILT4; boserolimab, anti-CD27; or lenvatinib), and EP for ES-SCLC. Methods: In this open-label platform study, patients (pts) were aged ≥18 y with previously untreated histologically or cytologically confirmed stage IV ES-SCLC (per AJCC v8) and ECOG PS 0 or 1. Pts were randomized 1:1:1 to receive MK-4830 800 mg Q3W (35 cycles; arm A), boserolimab 30 mg Q6W (18 cycles; arm B), or lenvatinib 8 mg (induction)/20 mg (maintenance) QD (arm C). All pts received pembro 200 mg Q3W (35 cycles) + etoposide 100 mg/m2 Q3W and cisplatin 75 mg/m2 Q3W or carboplatin AUC 5 mg/mL/min Q3W (4 cycles). Primary endpoints were ORR and PFS at 6 mo, both assessed per RECIST v1.1 by BICR. Secondary endpoints included DOR, PFS, OS, and safety. Results: 122 pts received ≥1 dose of study treatment (arm A, 43; B, 41; C, 38). At data cutoff (Sep 15, 2023), median follow-up was 14.1 (range, 6.1-25.7) mo. ORR was 65%, 71%, and 74% in arms A, B, and C, respectively; median DOR was 6.8, 4.7, and 7.1 mo. 6-mo PFS rates were 45%, 38%, and 54%, respectively (Table). AEs (any cause) occurred in 98% of pts in arm A and all pts in arms B and C; most commonly neutropenia and anemia. Serious AEs occurred in 30%, 37%, and 55%; grade ≥3 AEs in 86%, 83%, and 87% of pts; and grade 5 AEs in 5%, 7%, and 21%, respectively. Conclusions: 1L ES-SCLC treatment with pembro + EP and MK-4830, boserolimab, or lenvatinib was associated with similar antitumor activity as in KEYNOTE-604 with pembro + EP. No new safety signals were identified. TABLE 1. NAND Group A MK-4830 + Pembro + EP(n = 43) Group B boserolimab + Pembro + EP(n = 41) Group C Lenvatinib + Pembro + EP(n = 38) ORR (95% CI), % 65.1 (49.1-79.0) 70.7 (54.5-83.9) 73.7 (56.9-86.6) Median DOR (range), mo 6.8 (2.4-13.9) 4.7 (1.4+ to 16.4+) 7.1 (1.8 to 18.4+) PFS - 6-mo PFS rate (95% CI), % 45.2 (29.9-59.4) 37.8 (22.7-52.7) 54.2 (35.8-69.4) - Median PFS (95% CI), mo 5.5 (4.2-8.3) 5.5 (4.0-6.7) 7.2 (5.4-NR) Median OS (95% CI), mo 15.5 (8.3-NR) NR (13.2-NR) 15.8 (7.2-NR) ‘+’, no PD at the time of last disease assessment. NR, not reached. Citation Format: Delvys Rodríguez-Abreu, Maximillian Hochmair, Byoung Chul Cho, Tibor Csőszi, Talia Shentzer Kutiel, Veronika Müller, Myung-Ju Ahn, Dariusz Kowalski, Michele Maio, Vladimir Moiseyenko, Alejandro Navarro, Jianxin Niu, Andrea S. Fung, Carolin Lips, Heng Zhou, Bin Zhao, Humberto Lara-Guerra, Nir Peled. Results from KEYNOTE-B99: Phase 2 study of first-line (1L) pembrolizumab (pembro) plus investigational agents and chemotherapy (chemo) for extensive-stage small-cell lung cancer (ES-SCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT253.

Abstract 3605: Phase II study of pembrolizumab in conjunction with lymphodepletion, TIL ACT, and high- or low-dose IL-2 in patients with metastatic melanoma

Abstract Background: In metastatic melanoma (MM) patients (pts), adoptive cell transfer (ACT) using tumor-infiltrating lymphocytes (TIL) can yield lasting responses. However, TIL ACT with high-dose IL-2 has notable toxicities. Anti-PD1 (pembrolizumab) is FDA approved for MM treatment. Our study aimed to merge TIL infusion with anti-PD1 in two arms, comparing high (HD, arm 1) and low (LD, arm 2) IL-2 doses. Methods: After tumor harvest and TIL expansion, pts were lymphodepleted with cyclophosphamide and fludarabine, followed by infusion with their ex-vivo expanded TIL combined with IL-2 (arm 1: 720,000 IU/kg IV q 8 hrs up to 15 doses; arm 2: 2 million IU SC for 14 days). Pts were given 200 mg of IV anti-PD1 starting 21 days post-TIL infusion, followed by doses every 3 weeks for up to 2 years. Blood was taken before lymphodepletion and before the first two anti-PD1 doses for flow cytometry and cytokine analysis The primary endpoint of the study was determination of overall response rate by RECISTS 1.1 criteria. Enrollment aimed for 18 pts per arm, monitoring the primary ORR endpoint using a Bayesian rule. Enrollment would halt in any arm if the ORR dropped below 40%. Results: The median age was 50 years (n=14: 6 F and 8 M). Of these 14 pts, 8, 2, 2, and 2 had cutaneous, uveal, mucosal, or unknown primary melanoma. Pts had a median of 3 lines of prior therapies (range 1-6), including anti-PD-1 (n=13). In arm 1, one pt had a partial response (PR) for 10 months, 2 had stable disease (SD), 3 had progressive disease (PD), and 1 was not evaluable (NE). In arm 2, one pt had an ongoing PR for over 76 months, 1 had SD, and 5 had PD. Due to ORR <40% in each arm, enrollment was stopped after treatment of 14 pts. There was no significant different in progression-free survival or overall survival between the two arms (p=0.99 and p=0.71, respectively). In general, toxicity levels were comparable in both arms; however, pts in arm 2 had slightly lower grade 3 febrile neutropenia (57% vs. 71%) and shorter hospitalization (median 16 days vs. 18 days) than pts in Arm 1. While no correlation was observed between the phenotype of the TIL product and clinical response, both PR pts received high numbers of TIL (38.6 × 10^9 and 93.7 × 10^9; mean: 32.6 × 10^9 cells), with a high CD8+/CD4+ T cell ratio (284.7 and 2.7; median: 2.7). IL-2 dose did not affect circulating Treg frequency, phenotype, or proliferation by flow cytometry 3 weeks post TIL infusion. IL-2 dose was not associated with CD4+ non-Treg and CD8+ T cell phenotype or proliferation. Addition of anti-PD1 reduced expression of checkpoints but did not boost T cell proliferation. Conclusion: Our treatment strategy did not yield any distinct difference between low and high dose IL-2, suggesting the potential of low-dose IL-2 as an alternative. Anti-PD1 did not have any appreciable effect on immune states potentially due to the cohorts being comprised of a heavily pre-treated heterogenous pt population. Citation Format: Merve Hasanov, Simin Kiany, Marie-Andrée Forget, Roland L. Bassett, Michael A. Davies, Adi Diab, Jeffrey E. Gershenwald, Isabella C. Glitza, Jeffrey E. Lee, Anthony Lucci, Jennifer L. McQuade, Sapna P. Patel, Merrick I. Ross, Hussein A. Tawbi, Jennifer Wargo, Michael K. Wong, Chantale Bernatchez, Patrick Hwu, Cara Haymaker, Rodabe N. Amaria. Phase II study of pembrolizumab in conjunction with lymphodepletion, TIL ACT, and high- or low-dose IL-2 in patients with metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3605.

Safety of preventive HIPEC in combination with perioperative FLOT versus FLOT alone for resectable diffuse type gastric and gastroesophageal junction type II/III adenocarcinoma: An interim safety analysis from the phase III PREVENT trial of the AIO/CAOGI/ACO.

359 Background: Peritoneal relapse is seen in 60-70% of patients with diffuse type gastric cancer (gc), compared to 20-30% with intestinal type according to Laurens`s classification. Hyperthermic intraperitoneal chemoperfusion (HIPEC) is an increasingly used therapy method for patients (pts) with peritoneal metastases. The preventive use of HIPEC could represent an approach for diffuse type cell gc pts before macroscopic peritoneal seeding has evolved, since pts with operable disease are fit and may have potential risk of microscopic involvement, thus having a theoretical chance of cure with HIPEC even without the need for cytoreduction. Methods: This is a multicenter, randomized, controlled, open-label phase III study including a total of 200 pts with localized and locally advanced diffuse type cell adenocarcinoma of the stomach and type II/III gastroesophageal junction (i.e. ≥cT3 any N or any T N positive). A negative diagnostic laparoscopy before treatment and 3-6 pre-operative cycles of FLOT are a prerequisite for enrollment (Docetaxel 50 mg/m2; Oxaliplatin 85 mg/m2; Leucovorin 200 mg/m2; 5-FU 2600 mg/m2, q2wk). Pts were randomized 1:1 to receive surgery only and postoperative FLOT (Arm A-control arm) or surgery + intraoperative HIPEC (cisplatin 75mg/m2 solution at 42°C for 90 min) and postoperative FLOT (Arm B-experimental arm). Surgery is carried out as subtotal, total gastrectomy or transhiatal extended gastrectomy. The scope of the trial is to evaluate the efficacy as well as the safety and tolerability of the combination of perioperative chemotherapy combined with an intraoperative prophylactic HIPEC. Here, we show safety results from the pre-specified safety analysis after 20 pts had undergone surgical resection plus HIPEC and the corresponding 20 pts in the control arm. Results: Treatment arms were balanced regarding age, ECOG and tumor parameters like localization of the primary, of lymph nodes or cTN stage. Most pts in both arms received a subtotal or total gastrectomy. In 15 out of 20 arm B pts the HIPEC was 6 pts (30%) in Arm A and 7 pts (35%) in Arm B were seen with at least one SAE. Perioperative complications resulted in overall 7 SAEs in Arm A and in 4 SAEs in Arm B. One postoperative mortality (grade 5) was documented in Arm B due to septic complication. 11 pts showed no complications in both arms according to Clavien-Dindo-Classification. 6 pts in Arm A and 2 in Arm B showed grade 3. No patient was grade 4. Conclusions: The incidence of perioperative morbidity with surgical and/or medical complications were nearly equal in both treatment groups. The safety data showed no abnormalities or evidence increase in toxicity-rates including postoperative complications or increased severity of documented events within the experimental HIPEC arm. Clinical trial information: NCT04447352 .

A phase 1, open-label, multicenter study evaluating MK-1084 as monotherapy and in combination with other therapies in patients with KRAS G12C mutant advanced solid tumors.

TPS232 Background: Mutations in KRAS are one of the most prevalent oncogene mutations in human cancers, among which KRAS G12C mutations are one of the most frequently occurring. KRAS G12C inhibitors can slow tumor growth via attenuation of the KRAS signaling pathway. MK-1084, a selective KRAS G12C inhibitor, has demonstrated promising antitumor activity in preclinical studies. This phase 1, open-label, multicenter study (ClinicalTrials.gov, NCT05067283) is the first MK-1084 clinical study and aims to evaluate it as monotherapy and combination therapy in patients (pts) with advanced solid tumors. Findings from the initially enrolled study arms (Rojas et al. ESMO 2023; Abs 3156) indicated antitumor activity in pts with solid tumors receiving oral MK-1084 monotherapy QD or BID (25 to 800 mg total daily; arm 1) and pts with previously untreated non–small-cell lung cancer (NSCLC) with PD-L1 tumor proportion score ≥1% receiving MK-1084 from 25 to 400 mg total daily dose plus pembrolizumab 200 mg IV Q3W (arm 2). Toxicity was manageable during dose escalation of these 2 arms. Based on these initial findings, the study design has been updated to assess an alternate MK-1084 formulation and MK-1084 in combination with other therapies in KRAS G12C–mutated tumors. We present the study design for the new arms that include patients with gastrointestinal cancers. Methods: Eligible pts are aged ≥18 years with measurable disease per RECIST version 1.1 by investigator, ECOG performance status 0/1, adequate organ function, and advanced solid tumors (arm 3), or metastatic CRC with progression on 1 or 2 lines of prior therapy (arm 5), or previously untreated metastatic CRC (arm 6), all with KRAS G12C mutation. Pts in arm 3 receive the alternate MK-1084 formulation. Pts in arms 5 and 6 receive MK-1084 with one of the following: cetuximab 500 mg/m2 IV Q2W (arm 5); or cetuximab 500 mg/m2 IV Q2W, oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, and 5-fluorouracil per label IV Q2W (arm 6). Each arm has a safety run-in prior to expansion. The primary objective is to assess the safety and tolerability of MK-1084 as monotherapy and in combination with these other agents. Secondary endpoints include objective response and duration of response. AEs will be evaluated from baseline through 30 days after cessation of study treatment (90 days for serious AEs). Tumor imaging by CT or MRI will be performed at baseline, every 6 weeks up to week 18, every 9 weeks for the remainder of the first year, and then every 12 weeks. Response is assessed per RECIST version 1.1 by investigators. Analyses include pts who receive ≥1 dose of study treatment. Study enrollment began in December 2021. Clinical trial information: NCT05067283 .

A randomized controlled trial of CAPEOX vs observation in patients with early-stage colorectal cancer with positive MRD after curative surgery (CAREME).

TPS225 Background: Most patients (pts) with early-stage colorectal cancer (CRC) have a good prognosis, but some still relapse shortly after surgery. Effective methods to assess the risk of recurrence in these pts and guide adjuvant chemotherapy (ACT) decision-making are lacking. Increasing studies have shown that circulating tumor DNA (ctDNA) can detect minimal residual disease (MRD) and identify pts with a high risk of recurrence. ACT could improve survival of MRD-positive pts with stage Ⅱ CRC suggested by recent studies, whether it is appropriate for those with stage Ⅰ or clinically low-risk stage Ⅱ CRC remains unknown. Methods: CAREME is a multicenter randomized controlled clinical trial aimed at investigating the benefit of chemotherapy for MRD-positive pts with early-stage CRC. Pts with resected stage Ⅰ or Ⅱ CRC will be evaluated by oncologists. Those who did not receive neoadjuvant therapy and are deemed suitable for active surveillance (i.e., ACT is not needed) will undergo a postoperative ctDNA test using MinerVa MRD assay (a tumor-informed assay covering 769 cancer-related genes). Pts with mismatch repair-deficient tumors will be excluded and stage Ⅱ pts should have no traditional high-risk features according to clinical practice guidelines. Pts with positive ctDNA (N = 38) will be equally randomized into two groups: treatment group (Arm A) or surveillance group (Arm B). Arm A will receive 8 cycles of CAPEOX therapy while pts in Arm B will not receive any ACT; both groups will undergo ctDNA tests at 6 months after randomization and be followed up every 3 months. The primary endpoint is 18-month recurrence-free survival, and a key secondary endpoint is ctDNA clearance at 6 months after randomization. Tumor samples from the pts will be collected for MRD assay and exploratory research. Accrual started in February 2023. Support: Genecast Biotechnology Company. Clinical trial information: NCT05699746 .