Key Secondary Endpoints Research Articles

Evaluation of elranatamab vs EPd, PVd, or Kd in patients with relapsed or refractory multiple myeloma and prior anti-CD38–directed therapy: MagnetisMM-32.

TPS7576 Background: Elranatamab (ELRA), a humanized B-cell maturation antigen (BCMA)-CD3 bispecific antibody, has shown efficacy and manageable safety as a monotherapy in patients with relapsed or refractory multiple myeloma (RRMM). This study will evaluate ELRA monotherapy vs elotuzumab-pomalidomide-dexamethasone (EPd), pomalidomide-bortezomib-dexamethasone (PVd), or carfilzomib-dexamethasone (Kd) in patients with RRMM to determine whether ELRA can provide superior clinical benefit. Methods: MagnetisMM-32, a phase 3, open-label, multicenter, randomized study, will enroll ≈492 patients. Patients will receive ELRA (Arm A) or investigator’s choice of EPd, PVd or Kd (Arm B), until disease progression, unacceptable toxicity, withdrawal of consent, loss to follow-up, or study termination. Patients treated with ELRA will receive 2 step-up priming doses followed by weekly doses in a 28-day cycle. Patients who achieve a PR or better for ≥2 months will be eligible for reduced dosing frequency. Patients will be randomized 1:1 (stratified by prior line of therapy [1 vs 2 vs 3/4] and International Staging System disease stage [1/2 vs 3]). Key inclusion criteria include age of ≥18 years, prior multiple myeloma diagnosis with measurable disease (per IMWG criteria), evidence of progressive disease or failure to achieve a response to last line of multiple myeloma therapy, 1 to 4 prior lines of therapy including an anti–CD38 antibody–containing regimen (for ≥2 consecutive cycles) and a lenalidomide-containing regimen (for ≥2 consecutive cycles), adequate bone marrow function, and an ECOG performance status of ≤2. Key exclusion criteria include stem cell transplant ≤12 weeks prior to enrollment; active, uncontrolled infection; prior BCMA-directed or CD3-redirecting therapy; and unable to receive EPd, PVd, or Kd. The primary and key secondary endpoints are progression-free survival (PFS) by blinded independent central review (BICR) per IMWG criteria and overall survival (OS), respectively. Other secondary endpoints include PFS by investigator, objective response rate, duration of response, time to response by BICR, PFS on next line of therapy per IMWG criteria, MRD negativity rate, safety, pharmacokinetics of ELRA, immunogenicity, and health-related quality of life outcomes. The primary endpoint and OS will be compared statistically between treatment arms by stratified log-rank tests. Clinical trial information: NCT06152575 .

ARC-9: A randomized study to evaluate etrumadenant based treatment combinations in previously treated metastatic colorectal cancer (mCRC).

3508 Background: Adenosine mediated signaling via A2a and A2b receptors impairs activation, proliferation, and cytotoxic activity of effector T cells resulting in inhibition of antitumor activity. Adenosine receptor blockade may therefore enhance therapeutic efficacy of chemo/immunotherapy regimens. Etrumadenant (E) is an orally bioavailable, selective, A2a and A2b receptor antagonist that has demonstrated safety and clinical activity in solid tumors when combined with chemo/immunotherapy. ARC-9 (NCT04660812), a Phase Ib/II trial evaluating the safety and efficacy of E combined with zimberelimab (Z) (anti-PD-1 antibody), and FOLFOX/bevacizumab (bev) regimens or novel therapies in 3 cohorts of patients (pts) with mCRC. While FOLFOX rechallenge is frequently used in the management of mCRC, no prospective trials have been performed to date. Methods: Cohort B enrolled pts who previously progressed on both oxaliplatin and irinotecan containing regimens.Pts were randomized 2:1 to EZFB: E (150 mg orally [PO] once daily [QD]) + Z (240 mg intravenous [IV] once every 2 weeks [Q2W]) + mFOLFOX-6 + bev (5 mg/kg IV Q2W), or regorafenib (rego) (160 mg PO QD [days 1-21 every 4 weeks]). Pts who progressed on rego were allowed to crossover to EZFB. The primary endpoint is progression-free survival (PFS) per RECIST 1.1 and overall survival (OS) is a key secondary endpoint. Results: In Cohort B, 112 pts were randomized. Baseline characteristics are comparable between arms. As of 13 Nov 2023, with median follow-up of 20.4 months (mo), EZFB demonstrated statistically significant improvement in PFS (HR 0.27, 95% CI 0.17-0.43, p < 0.0001) and OS (HR 0.37, 95% CI 0.22-0.63, p = 0.0003) vs rego (Table). EZFB had an acceptable safety profile, consistent with the known FOLFOX/bev toxicity profile with no deaths related to study treatment in either arm. Conclusions: In this randomized phase II clinical trial, EZFBsignificantlyimproved efficacy outcomes compared to rego in refractory mCRC pts previously treated with 5-FU, oxaliplatin and irinotecan regimens with no unexpected toxicities. Further investigation of this promising regimen is warranted given the clinically meaningful PFS and OS improvement. Table Clinical trial information: NCT04660812 . [Table: see text]

A propensity-matched analysis of the efficacy and safety of neoadjuvant inetetamab and pertuzumab with paclitaxel and carboplatin (TCbIP) on locally advanced HER2-positive breast cancer.

e12609 Background: Inetetamab is an Fc segment-modified innovative anti-HER2 monoclonal antibody. It has been proven to be effective and safe in HER2-positive advanced breast cancer. However, its efficacy and safety in the neoadjuvant treatment of HER2-positive locally advanced breast cancer (LABC) remains to be validated. This study aimed to evaluate the efficacy and safety of Inetetamab-based neoadjuvant therapy (TCbIP). Methods: In this prospective cohort study, we investigated the efficacy and safety of TCbIP in neoadjuvant therapy for HER2-positive LABC, and compared with TCbHP regimen (trastuzumab combined with pertuzumab, paclitaxel, and carboplatin) with propensity score matching (PSM). Thirty-four patients (clinical stage IIA-IIIC, HER2-positive LABC) were prospectively enrolled in this study and treated with the TCbIP regimen. The primary endpoint was total pathological complete response (tpCR). Adverse events (AEs), objective response rate (ORR), and near-pCR were key secondary endpoints. Results: The pCR rate of 28 patients who finished surgery was 60.7%, and was comparable and slightly higher (60.7% vs. 53.6%, P = 0.510) than the TCbHP group in PSM. The ORR was 96.4% and DCR reached 100.0%. The most common ≥grade 3 AE was neutropenia (21.4% vs. 11.9%, P = 0.350). No significant reduction in left ventricular ejection fraction was observed, and no patient withdrew from treatment due to AEs. Conclusions: Neoadjuvant therapy with TCbIP resulted in good efficacy and safety in patients with HER2-positive LABC, and might be another promising option for neoadjuvant treatment. Clinical trial information: NCT05749016 .

Study of the Bria-IMT regimen and CPI vs physicians' choice in advanced metastatic breast cancer (BRIA-ABC).

TPS1137 Background: BriaCell (BC) human immortalized cell lines have been engineered to trigger robust immune responses and deliver efficacy through diverse mechanisms, including adaptive (involving T-cells) and innate responses (dendritic and NK cells). BC can match patients’ HLA antigens for optimal effectiveness. BC works by several mechanisms, including direct antigen presentation and activation of CD4+ T-cells. When combined with an immune checkpoint inhibitor, the BC regimen has demonstrated clinical benefit in 54 heavily treated MBCs. Most pts whose disease has progressed after checkpoint inhibitor (CPI) therapy showed similar or improved PFS compared to the patient's last treatment regimen. Disease control after prior antibody-drug conjugates (ADCs) has been observed in 40% of patients, and clinical benefit has been seen in 5/7 patients with untreated intracranial metastases. CD8+ Immuno PET shows an increase in CD8+ tumor infiltrating lymphocytes suggesting systemic activation and infiltration into lymphoid organs and metastatic sites. Sequencing of CPI with BC and the latest phase 3 formulation are associated with improved clinical outcomes, including OS (median 13.4 months), PFS, and CBR, which are reflected in the design of this ongoing pivotal registration enabling Phase 3 study [doi:10.1158/1538-7445.sabcs22-p3-07-12]. Methods: Multicenter randomized, open label Bria-IMT regimen (with SV-BR-1-GM cells) plus CPI vs Treatment of Physicians' Choice (TPC) in MBCs with no approved curative therapies available. ECOG <2 allowed with no limit on prior therapies. Eligibility encompasses all MBC subtypes including pts with CNS metastases. Prior immune therapy is allowed if administered more than 21 days before the first cycle of Bria-IMT; treatments within 21 days preclude participation. Initial randomization will be 1:1:1 to the Bria-IMT regimen + CPI (combination), TPC, and the Bria-IMT regimen alone (monotherapy). There will be 100 sites across the US, Canada, and ex-NA for 404 total evaluable pts. The Bria-IMT regimen includes: Day -2 Cyclophosphamide 300mg/m2, Day 0 20 million irradiated SV-BR-1-GM cells intradermally, and 0.1mcg peg α interferon intra-dermally (Day 2 or 3) into each Bria-IMT inoculation site. After the first 150 pts have enrolled, the monotherapy arm will be discontinued. Bria regimen + CPI arms treatment cycles occur q3w. CPI infusion is given every cycle between Day –3 to Day 3 TPC cycle details will be according to the site's SOC. Imaging assessment will be q6w x2 then q8w. The primary endpoint is overall survival with an interim analysis at 144 events targeting a hazard ratio of 0.6. Key secondary endpoints will include PFS, ORR, CBR, CNS event free survival, and TWiST (time without symptoms or toxicities). Safety analysis will be ongoing. Patient-reported outcomes will be incorporated to assess subjective treatment effects. Clinical trial information: NCT06072612 .

Long-term survival outcomes of patients (pts) with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) treated with brexucabtagene autoleucel (brexu-cel) in ZUMA-3.

6531 Background: Brexu-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for pts ≥18 y with R/R B-ALL in the US (≥26 y in the EU). In the 3-y follow-up of ZUMA-3, median overall survival (OS) was 25.6 mo (N=78). Survival benefit was seen regardless of age, prior treatment, or subsequent allogeneic stem cell transplant (sub alloSCT) status (Shah et al. ASCO 2023. #7023). Here we report 4-y survival outcomes for ZUMA-3. Methods: Eligible pts (≥18 y) had R/R B-ALL and received brexu-cel (1×106 CAR T cells/kg) after leukapheresis and lymphodepleting chemotherapy. The primary endpoint was overall complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate per independent review with OS as a key secondary endpoint. Descriptive statistics are reported for post hoc exploratory subgroup analyses. Results: As of July 23, 2023, median follow-up time in Phase 1 and 2 pts who received the pivotal dose of brexu-cel (N=78) was 53.6 mo (range 44.7-82.3). Median OS (95% CI) was 25.6 mo (16.2-60.4) in all treated pts and 47.0 mo (23.2-not estimable [NE]) in pts with CR/CRi (n=57). In pts <26 y (n=15), median OS (95% CI) was 23.2 mo (9.0-NE) and was 26.0 mo (15.9-NE) in pts ≥26 y (n=63). Median OS (95% CI) in pts with 1 prior therapy (n=15) was 60.4 mo (7.6-NE) and was 25.4 mo (15.9-47.0) in pts with ≥2 prior therapies (n=63). Medians for OS (95% CI) in pts with (n=38) and without (n=40) prior blinatumomab (blina) were 15.9 (8.3-26.0) and 60.4 mo (18.6-NE), respectively. Median OS (95% CI) was 36.3 mo (10.2-NE) in responders who went on to sub alloSCT (n=14) and 60.4 mo (23.2-NE) in those who did not (n=43). The 48-mo OS rate was 40% (95% CI, 28-52) in all pts but appeared lower in pts with prior blina (24%; Table). No new adverse events or deaths occurred since the prior analysis. Grade ≥3 infection rates since the start of study appeared higher in pts <26 y and in pts with prior blina (Table). Rates of non-relapse mortality (NRM) and relapse-related mortality (95% CI) at 48 mo were 25% (15-37) and 34% (24-45; N=78), respectively. Of note, 6/17 NRM events (35%) occurred in pts with sub alloSCT. Conclusions: After >4 y follow-up, pts in ZUMA-3 continued to experience OS benefit regardless of age, prior therapy, or sub alloSCT status, though pts with prior blina had a numerically lower 48-mo OS rate. Small subgroups and unbalanced pt characteristics limit interpretation of these results. No new safety signals were observed. Further studies are needed to fully assess the impact of age, prior therapies, and sub alloSCT on outcomes after brexu-cel. Clinical trial information: NCT02614066 . [Table: see text]

A first-in-human study to evaluate a personalized neoantigen-based mRNA-loaded dendritic cell vaccine, in combination with ablation, in patients with hepatocellular carcinoma.

e14513 Background: Local recurrence of Hepatocellular Carcinoma (HCC) following potentially curative resection or ablation is an inevitable risk. T cells recognizing neoantigens are present in most cancers including HCC and offer a specific and highly immunogenic target for the personalized vaccination as an adjuvant therapy. The purpose of this study is to evaluate the safety and T cell immune response of a personalized neoantigen-based mRNA loaded dendritic cell (DC) vaccine (LK101) combined with regular ablation in patients with HCC (NCT03674073). Methods: Each patient’s fresh tumor biopsy and matched peripheral blood sample were subjected to whole-exome sequencing and RNA-sequencing. Following determination of somatic mutations and gene expression, up to 30 in silico–predicted potential neoantigens were selected with bioinformatic tool. DCs were generated from the monocytes enriched by leukapheresis, followed by transfection with neoantigen-encoding mRNA through electroporation. In total, 7 doses of LK101 were administered at 1.5×107 cells/injection intradermally with 4-dose priming weekly and 3 boosters in 4-week intervals. The primary endpoint of the clinical study was safety, and key secondary endpoints were immunogenicity, overall survival and recurrence. 24 HCC patients at HKLC stage IIa were enrolled 1:1 to ablation control arm and ablation combined with DC (LK101) arm. Results: The study was completed, patients were followed up for a median of 48.4 months and 38.8 months in vaccination arm and control arm. All of adverse events were Grade 1-2. Most frequent treatment-related adverse events are injection site reactions, inclusive of local pain (63.6%), itch (27.3%) and others (27.3%), such as redness and edema. 3 patients in ablation control arm died, whereas all vaccinated patients survived. The 1-year and 2-year recurrence rates in vaccination arm compared with control arm are 18.2%, respectively. LK101 induced neoantigen-specific T cell responses were investigated by ELISpot analysis. Overall, all patients elicited at least one measurable response. Immune responses to 60-90% of neoantigen peptides were seen post vaccination across patients. Both preexisting immune response and De Novo immune response that targeted neoantigens were observed in vaccinated patients. Moreover, both CD4 and CD8 positive effector memory T cells showed the trend of increase, and PD-1 positive T cells reduced in peripheral blood of patients after vaccination. Conclusions: Combination of LK101 with ablation therapy has a manageable safety profile, showing the evidence of immune activation and potential of prolonged survival. In combination with regular ablation, neoantigen based mRNA loaded DC vaccine is a promising immunotherapy for the treatment of HCC. Clinical trial information: NCT03674073 .

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]

A randomized, multicenter, open-label, phase 2 study of TRK-950 in combination with ramucirumab and paclitaxel as second-line therapy in patients with Caprin-1 positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma.

TPS4181 Background: Caprin-1 is strongly expressed on the cell membrane of many cancer types including G/GEJ and on cancer stem cells. High expression is associated with enhanced in vitro colony-forming activity and in vivo tumorigenicity. TRK-950 is a first in class humanized antibody targeting CAPRIN-11). In the phase I study (NCT02990481), TRK-950 was well tolerated as monotherapy with no DLTs and MTD not reached at doses of 3-30mg/kg IV weekly. Subsequently the Phase 1b study demonstrated that TRK-950 was well tolerated with a high potential for synergistic anti-tumor activity when used in combination with standard of care treatment(s) in selected advanced solid tumors (NCT03872947). Specifically, Regimen D which evaluated TRK-950 in combination with Ramucirumab and Paclitaxel in G/GEJ showed a DCR of 100% in all nine patients receiving 10 mg/kg and partial responses were seen in 5/9 (55%) patients. Caprin-1 strong expression was observed in 4/9 patients and an ORR of 100% was seen in those patients2). A Phase II clinical trial in gastric/GEJ cancer patients with strong Caprin-1 expressions is now enrolling patients. Methods: The phase II study is a multi-national, open-label, randomized, multicenter study evaluating the efficacy of TRK-950 in combination with ramucirumab (Ram) + paclitaxel (PTX ) as compared with Ram + PTX treatment alone in patients with previously treated metastatic G/GEJ adenocarcinoma (NCT06038578). Patients enrolled across 10 sites in Japan, South Korea and the United States are randomized 1:1:1 by the permuted block method to (arm A) TRK-950 5mg/kg plus Ram + PTX, (arm B) TRK-950 10mg/kg plus Ram + PTX or (arm C) Ram + PTX alone. Inclusion criteria include patients with Caprin-1 positive (cutoff; 30% at ≥ 2+ staining) advanced/metastatic G/GEJ adenocarcinoma who have received first line therapy. Key exclusion criteria include HER2 positive disease. The primary endpoint is progression free survival (PFS) based on Independent Central Review (ICR) assessment per RECIST v1.1. Key secondary and exploratory endpoints include overall survival (OS), ORR, DoR, and biomarker evaluation. An interim analysis will be performed after 105 patients are randomized in stage 1 to determine the optimal dose of TRK-950 (5mg/kg or 10mg/kg) that will be evaluated in arm stage 2. In total 146 patients will be enrolled (40 patients in one arm and each 53 patients in two arms). This study opened in September 2023. 1. Okano F, et al. Cancer Res Commun. 2023 Apr 18;3(4):640-658. 2. Cassier P, et al. J Clin Oncol. 2023 Vol. 41, No. 4, suppl. Clinical trial information: NCT06038578 .

EPCORE FL-2: Phase 3 trial of epcoritamab with rituximab and lenalidomide (R2) vs chemoimmunotherapy or R2 in previously untreated follicular lymphoma.

TPS7084 Background: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma. Most patients with advanced-stage FL in need of systemic therapy are treated with an anti-CD20 monoclonal antibody (eg, rituximab [R] or obinutuzumab [G]) with cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] or bendamustine [benda]). Recent studies have shown R plus lenalidomide (R2) is a potent FL treatment in the 1L and relapsed or refractory (R/R) settings and is a promising backbone for combination therapies. Epcoritamab, a subcutaneous CD3xCD20 bispecific antibody, received breakthrough therapy designation by the FDA for R/R FL after ≥2 lines of systemic therapy. In the phase 1/2 trial (NCT04663347), epcoritamab plus R2 demonstrated high complete response (CR) rates in the 1L and R/R settings. The objective of this trial is to evaluate the safety and efficacy of 1L epcoritamab plus R2 vs CIT in patients with FL. Methods: EPCORE FL-2 (NCT06191744) is a global, randomized, open-label phase 3 trial. Eligible adult patients must have CD20+ histologically confirmed classic FL (previously grade 1–3A), stage III or IV disease (or bulky stage II), and in need of systemic treatment by meeting GELF criteria. Approximately 1080 patients will be randomized to 3 treatment arms (Table). Patients achieving CR or PR upon 6 cycles will move to epcoritamab on day 1 of cycles 7–12 (28-day cycles) and 13–21 (56-day cycles). After 120 weeks of treatment, patients will be followed for progression and survival. Dual primary endpoints will be CR rate at 30 months and progression-free survival in arm A vs arm B. Key secondary efficacy endpoints include overall survival, minimal residual disease negativity, and changes in patient-reported outcomes on the physical functioning scale of the European Organization for Research and Treatment of Cancer Quality of Life-C30 Questionnaire from baseline to week 25. Safety endpoints include incidence and severity of adverse events (AEs), including AEs of special interest (cytokine release syndrome, immune effector cell–associated neurotoxicity syndrome, and clinical tumor lysis syndrome). The study is open for enrollment. Clinical trial information: NCT06191744 . [Table: see text]

Phase 3 randomized study of isatuximab (Isa) plus lenalidomide and dexamethasone (Rd) with bortezomib versus isard in patients with newly diagnosed transplant ineligible multiple myeloma (NDMM TI).

7501 Background: CD38 targeting immunotherapy is approved in combination with lenalidomide and dexamethasone in NDMM TI and considered the current standard of care (SOC). The best treatment combinations are important in NDMM TI, as outcomes worsen with successive line of therapy. To improve current SOC, we evaluated the added value of prolonged use of bortezomib for 18 months with reduced intensity weekly schedule to IsaRd, with the intent to demonstrate the impact of a PI in a quadruplet regimen to improve depth of response. In BENEFIT/IFM2020-05 study (NCT04751877), we investigated efficacy and safety of IsaRd vs Isa-VRd in NDMM TI. Methods: BENEFIT is a prospective, multicenter, randomized, parallel trial. Patients aged 65-79, non-frail, with NDMM TI were randomized 1:1 and stratified by age, high-risk cytogenetic and center. Isa-VRd arm received V (1.3 mg/m2 SC weekly up to c12 (c), bimonthly up to c18); both arms received Isa (10 mg/kg IV weekly and bimonthly up to c12, then monthly), R (25 mg), and d (20 mg up to c12). The primary endpoint was minimal residual disease (MRD) 10-5 negative rate (NGS) at 18 months from treatment start analyzed in ITT. Key secondary endpoints included survival times (OS, PFS, EFS, TTNT), response rates and durations, MRD endpoints, and safety (using NCI CTCAE v5.0). Results: At data cutoff date (02 Feb 2024), 270 patients (135 per arm) were recruited. Patients baseline characteristics were well balanced across arms, overall median age was 73.2 years [IQR. 71;76], 90 patients (33%) were >75 years, 23 (9%) had high-risk cytogenetic (IFM score >1), 181 (76%) had R-ISS2+3, and 47 (17%) had impaired renal function (eGFR <60 mL/min). MRD negativity rates at 10-5 at 18 months were significantly higher in Isa-VRd arm compared to IsaRd arm (47% vs 24%, OR for negative MRD =2.96 [95%CI. 1.73 – 5.07, p<0.001]. The MRD benefit was consistent across subgroups. At 21.2 months median follow-up, 33 (12%) patients had relapsed and 20 (7%) had died, and no significant difference were observed across arms, yet. The addition of weekly “light” schedule of bortezomib did not significantly affect relative dose intensity of IsaRd. Forty-four (33%) patients presented with neurological adverse events grade ≥2 in the Isa-VRd vs 27 (20%) in IsaRd arm. Conclusions: Isa-VRd significantly deepened responses including a significant increase of the MRD negative rate at 10-5 vs IsaRd. The safety profile is consistent with addition of bortezomib. This study supports Isa-VRd as a new standard of care for NDMM TI non-frail patients. Clinical trial information: NCT04751877 . [Table: see text]

A phase 2, open-label, single-arm, prospective, multicenter study of nab-sirolimus plus letrozole in advanced or recurrent endometrioid endometrial cancer.

TPS5640 Background: This clinical trial is designed to evaluate the antitumor activity of nab-sirolimus in combination with letrozole in patients with advanced or recurrent endometrioid endometrial carcinoma (EEC). Despite recent pivotal data demonstrating improved outcomes with immunotherapy plus chemotherapy, regardless of mismatch repair status, alternative nonchemotherapy-based treatment options for patients with advanced or recurrent EEC remain necessary. Dysregulation of mTOR signaling is implicated in the pathology of EEC, in which >80% harbor PTEN or PI3K/Akt/mTOR pathway alterations. Moreover, crosstalk between mTOR and estrogen receptor signaling pathways is associated with endocrine therapy resistance. GOG-3007 and other phase 2 studies have demonstrated that the combination of conventional mTOR inhibitors (mTORis) and endocrine therapy provides clinical benefit in patients with EEC. nab-Sirolimus is an mTOR inhibitor that uses albumin-bound sirolimus nanoparticles given by IV and is approved by the US FDA for malignant perivascular epithelioid cell tumor. Preclinical data of nab-sirolimus demonstrated improved tumor accumulation, mTOR inhibition, and tumor growth suppression compared with conventional mTORis. We hypothesize that the simultaneous inhibition of mTOR and ER with nab-sirolimus and letrozole, respectively, may provide a signal of synergistic antitumor activity in patients with recurrent EEC. Methods: In this phase 2, open-label, single-arm, multicenter study (NCT05997017), nab-sirolimus (100 mg/m2, intravenous, on days 1 and 8 of each 21-day cycle) and letrozole (2.5 mg, oral, daily) are administered to patients (~29 planned, Simon’s 2-stage design) with clinically confirmed, advanced, or recurrent EEC. Eligibility criteria include age ≥18 years, ≤1 prior chemotherapy-based regimen in the advanced, metastatic, or recurrent setting, prior adjuvant chemotherapy is permitted, Eastern Cooperative Oncology Group performance status score 0 or 1, naive to mTORi, and measurable disease (per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1). The primary endpoint is best overall response rate by RECIST v1.1. Key secondary endpoints include duration of response, disease control rate (defined as complete response plus partial response plus stable disease of ≥12 weeks after start of treatment), progression-free survival, overall survival, and safety. Exploratory endpoints include correlation of baseline molecular biomarkers with clinical outcomes. The trial is open for enrollment. Clinical trial information: NCT05997017 .

TRITON: Phase 3b study of tremelimumab (T) + durvalumab (D) vs pembrolizumab (P), in combination with chemotherapy (CT), in non-squamous (NSQ) metastatic NSCLC (mNSCLC) with STK11and/or KEAP1 and/or KRAS mutations.

TPS8655 Background: Mutations in STK11 and KEAP1, present in approximately 20% and 15% of patients (pts) respectively with NSQ mNSCLC, lead to an immunosuppressive tumor microenvironment and are associated with inferior clinical outcomes with anti-PD-(L)1 based chemo-immunotherapy, especially when co-mutated with KRAS. Pts with tumors bearing STK11, KEAP1and/or KRAS mutations may benefit from combinations with CTLA-4 inhibitors, aimed at increasing immune responses. In the phase 3 POSEIDON trial (NCT03164616), first-line (1L) T+D+CT significantly improved overall survival (OS; HR 0.77 [95% CI 0.65–0.92]; P=0.0030) vs CT. These results were maintained after a median follow-up of >5 years. Subgroup analyses showed sustained OS improvement with T+D+CT vs CT in pts with mNSCLC with STK11 (NSQ), KEAP1(all histologies, due to small sample size), and KRAS (NSQ) mutations (HR [95% CI] 0.57 [0.32–1.04), 0.43 [0.16–1.25], and 0.55 [0.36–0.83], respectively). The TRITON study will further investigate the signal of efficacy observed in the POSEIDON subgroup analysis. The study will compare T+D+CT vs P+CT (a standard treatment for NSQ mNSCLC) in pts with STK11 and/or KEAP1 and/or KRASmutations. The results will help to inform clinical practice and to establish a biomarker-driven treatment strategy for these difficult-to-treat pts. Methods: TRITON (NCT06008093) is a phase 3b, multicenter, open-label, 2-arm parallel randomized study. Eligible pts, aged ≥18 years, must have NSQ mNSCLC (no EGFR or ALK alterations), with STK11, KEAP1, or KRAS mutations/co-mutations, no prior systemic therapy for mNSCLC, and ECOG performance status of 0/1. Approximately 280 pts will be randomized 1:1 to receive either T+D+CT or P+CT. In the T+D+CT arm, pts will receive T (75 mg) + D (1500 mg) + carboplatin (AUC 5 or 6)/cisplatin (75 mg/m2) + pemetrexed (500 mg/m2) every 3 weeks (Q3W) for 4 cycles (a fifth dose of T [75 mg] will be given in combination with D, post-platinum at week 16), followed by maintenance D (1500 mg) + pemetrexed (500 mg/m2) Q4W until disease progression (PD). In the P+CT arm, pts will receive P (200 mg) + carboplatin (AUC 5 or 6)/cisplatin (75 mg/m2) + pemetrexed (500 mg/m2) Q3W for 4 cycles, followed by maintenance P (200 mg) + pemetrexed (500 mg/m2) Q3W until PD, for up to 24 months. Randomization is stratified by mutation type ( KRAS [without STK11 or KEAP1] mutations are capped at 33% of the total sample) and tumor PD-L1 expression (≥1% vs <1%). Primary endpoints are OS in all pts and in the subset with STK11 or KEAP1 mutations/co-mutations. Key secondary endpoints include OS rates at 12 and 24 months, progression-free survival, objective response rate, duration of response (all RECIST v1.1; investigator-assessed) and safety/tolerability (CTCAE v5.0). Enrollment is ongoing. Clinical trial information: NCT06008093 .

Sotorasib versus pembrolizumab in combination with platinum doublet chemotherapy as first-line treatment for metastatic or locally advanced, PD-L1 negative, KRAS G12C-mutated NSCLC (CodeBreaK 202).

TPS8653 Background: The 5-year progression free survival (PFS) rate of patients with metastatic, PD-L1 negative, non-small cell lung cancer (NSCLC) remains poor, ranging from approximately 2% to 10% with standard immunotherapy-based treatment regimens. Based on promising anti-tumor activity in the phase 1 CodeBreaK 101 study, with partial responses observed in 62% (8/13) of PD-L1 negative patients in the first-line setting, we hypothesize that sotorasib plus platinum doublet chemotherapy will demonstrate durable clinical response and improved outcomes in this population. CodeBreaK 202 (NCT05920356) is a global phase 3 randomized study evaluating the efficacy of sotorasib versus pembrolizumab in combination with platinum doublet chemotherapy as first-line treatment for metastatic or locally advanced, PD-L1 negative, KRAS G12C-mutated NSCLC. Methods: Patients will be randomized 1:1 to either sotorasib 960 mg once daily or pembrolizumab administered in combination with carboplatin and pemetrexed for 4 cycles, followed by maintenance treatment with sotorasib or pembrolizumab administered in combination with pemetrexed. Key eligibility criteria include treatment-naïve metastatic or locally advanced stage IIIB/C disease that is not amenable to definitive chemoradiation, PD-L1 <1% expression, presence of KRAS G12C mutation, non-squamous tumor histology, and absence of actionable genomic alterations such as EGFR mutations and ALK rearrangements. Patients with both treated and untreated brain metastases are eligible if clinically asymptomatic. The primary endpoint is PFS per RECIST v1.1 by blinded independent central review (BICR). Key secondary endpoints include overall survival and objective response rate. Exploratory endpoints include intra-cranial PFS per RANO-BM criteria. Approximately 750 patients are planned to be enrolled and recruitment began on November 18, 2023. Contact Amgen Medical Information for more information: medinfo@amgen.com . Clinical trial information: NCT05920356 .

Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer: Overall survival and updated 5-year results from the randomized DYNAMIC trial.

108 Background: Previous results of the DYNAMIC study demonstrated that a ctDNA-guided approach versus standard management in stage II colon cancer (CC) reduced adjuvant chemotherapy (ACT) use without compromising 2-year recurrence-free survival (RFS). MMR status defines two distinct subsets of stage II CC. Here, we report the impact of ctDNA burden, end of ACT (EOT) ctDNA, and updated survival data including overall survival (OS). Methods: DYNAMIC is a multi-center randomized phase II trial. Eligible patients (pts) had resected stage II CC and were suitable for ACT. Pts were randomly assigned 2:1 to ctDNA-guided management or standard management (clinician-guided based on conventional criteria). For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery with a tumor-informed assay prompted oxaliplatin-based or fluoropyrimidine ACT; ctDNA-negative pts were not treated. Between Aug 2015 and Aug 2019, 302 received ctDNA-guided and 153 standard management. The primary endpoint was RFS, with a non-inferiority margin of 8.5%. Pre-specified key secondary endpoints were ACT use and OS, with an additional secondary endpoint of ctDNA clearance rate. Results: With a median follow-up of 59.6 months (IQR 55.0–61.5), 5-year RFS were 88% and 87% with ctDNA-guided and standard management, respectively (difference 1.1%, 95% confidence interval, -5.8% to 8.0%). 5-year OS for ctDNA-guided treatment was 93.8% and standard management 93.3% (HR 1.05; 95% CI, 0.47 to 2.37; P = 0.887). 5-year OS was significantly worse in treated ctDNA-positive versus untreated ctDNA-negative pts (85.6% vs 95.3%, HR 3.30; 95% CI, 1.02 to 9.05; P = 0.014). The 5-year OS for ctDNA-negative T3 and T4 disease were 96.0% and 90.6%, respectively (HR 2.45; 95% CI, 0.65 to 9.25; P = 0.171). For treated ctDNA-positive pts, ctDNA clearance was observed at EOT in 35/40 (87.5%). The 5-year RFS for EOT ctDNA clearance vs ctDNA persistence were 85.2% and 20.0%, respectively (HR 15.4; 95% CI, 3.91 to 61.0; P < 0.001). Pts with ≥ 0.38 (the median) mutant tumor molecules (MTM/mL) had a lower ctDNA clearance rate and worse RFS than pts with < 0.38 MTM/mL (ctDNA clearance 75% vs 100%, P = 0.047; 5-year RFS 58.9% vs 95.2%, HR 10.62, P = 0.005). Post-op ctDNA was detected in 5/59 (8.5%) of dMMR and 40/235 (17%) of pMMR cases. In an exploratory analysis, ctDNA clearance was observed in 3/4 (75%) and 32/36 (89%) of dMMR and pMMR cases, respectively. Conclusions: Mature outcome data confirms the previous finding of non-inferiority of RFS with a ctDNA-guided approach to ACT for stage II CC. For ctDNA-positive pts, the post-surgery mutation burden provides additional prognostic information, as does the EOT ctDNA result. Additional data is needed to define any differential impact of ACT by MMR status. This data supports a role for ctDNA analysis, including serial sampling, in the management of stage II CC. Clinical trial information: ACTRN12615000381583 .

CELESTIAL-TNCLL: An ongoing, open-label, multiregional, phase 3 study of sonrotoclax (BGB-11417) + zanubrutinib vs venetoclax + obinutuzumab for treatment-naïve (TN) CLL.

TPS7087 Background: The combination of venetoclax (ven), the first-generation BCL2 inhibitor, and ibrutinib, a BTK inhibitor, has demonstrated efficacy in patients with CLL (Wierda et al. J Clin Oncol. 2021); however, the toxicity profile of this regimen suggests a need for a more tolerable BTK/BCL2 inhibitor combination. Sonrotoclax, a next generation BCL2 inhibitor, is a more selective and more pharmacologically potent inhibitor of BCL2 than venetoclax. In a phase 1 study in patients with TN CLL treated with sonrotoclax + zanubrutinib, efficacy data was promising with ORR and 1-year progression-free survival (PFS) rates of 100% and deep responses based on undetectable measurable residual disease at <10-4 sensitivity (uMRD4). The most common grade ≥3 TEAE was neutropenia, and no tumor lysis syndrome or cardiac toxicity was observed (Tam et al. Blood. 2023). Zanubrutinib, a next-generation BTK inhibitor, significantly improved PFS and had a more tolerable safety profile, including fewer cardiac adverse events vs ibrutinib in a randomized, head-to-head study of patients with CLL/SLL (Brown et al. N Engl J Med. 2023). Presented here is the design of a phase 3 trial aimed at comparing the efficacy of sonrotoclax + zanubrutinib vs ven + obinutuzumab (obi) in patients with TN CLL. Methods: CELESTIAL-TNCLL (BGB-11417-301; NCT06073821) is a randomized, open-label, phase 3 study. Eligible patients must have previously untreated CLL that requires treatment per 2018 iwCLL criteria, measurable disease by CT/MRI, an ECOG performance score of 0-2, and adequate hematologic and organ function. Approximately 640 patients will be randomized 1:1 to receive either 3 cycles of zanubrutinib monotherapy (320 mg total daily dose, orally), followed by zanubrutinib + sonrotoclax for 12 cycles, or standard ven + obi treatment for 12 cycles. Randomization will be stratified by age (<65 vs ≥65 years) and IGHV and del(17p)/ TP53 mutation status. The primary endpoint is PFS as assessed by independent review committee (IRC) according to 2018 iwCLL guidelines with modifications for treatment-related lymphocytosis for patients with CLL (Cheson et al. 2012). Key secondary endpoints include complete response rate (CRR), defined as CR or CR with incomplete hematopoietic recovery, assessed by IRC; rates of uMRD4 in bone marrow and peripheral blood at the first post-treatment follow-up visit based on next-generation sequencing by clonoSEQ; and overall survival. Other secondary endpoints include PFS as assessed by investigator (INV); CRR by INV; rate of uMRD4 based on flow cytometry; overall response rate by IRC and INV; duration of response by IRC and INV; patient-reported outcomes; and safety and tolerability. Recruitment is ongoing. Clinical trial information: NCT06073821 .

FURTHER: A global study to evaluate furmonertinib in patients with EGFR mutant NSCLC including uncommon EGFR mutations (FURMO-002).

TPS8666 Background: Furmonertinib (AST2818) is an oral, highly brain-penetrant, and broadly active mutation-selective epidermal growth factor receptor ( EGFR) inhibitor engineered for broad activity and selectivity across EGFRmutations (mts) (1). Furmonertinib is approved in China for first-line advanced NSCLC with EGFR Ex19del or L858R mts based on the progression-free survival benefit observed in the Phase 3 study versus gefitinib (FURLONG). Furmonertinib has also demonstrated promising interim efficacy and safety in patients (pts) with NSCLC harboring EGFR exon 20 insertion (ex20ins) mts with a confirmed overall response rate (ORR) of 78.6% (n=28) by blinded independent central review (BICR) and a preliminary median duration of response (DoR) of 15.2 months in the front-line setting (FAVOUR study; see Han et al., WCLC 2023). Furmonertinib recently obtained FDA Breakthrough Therapy Designation for the treatment of pts with advanced NSCLC with EGFR ex20ins mts. P-loop and αC-helix Compressing (PACC) mts represent another subset of uncommon EGFR mts (2) that are similar to ex20ins mts in narrowing the drug-binding pocket; including G719X, S768I, E709X, L747X, V774M. Preclinical data indicating that furmonertinib is potent in models harboring EGFR PACC mts Developing efficacious, well-tolerated, and CNS-penetrant medicines for NSCLC pts with EGFR ex20ins mts and PACC mts remains an unmet need. Methods: FURTHER (FURMO-002) is the first global trial evaluating furmonertinib in NSCLC pts with EGFR and HER2 mts in North America, Europe, and the Asia-Pacific. FURTHER is a phase 1b, open-label, multicenter study in which pts will be treated orally with furmonertinib daily. For Stage 1 dose-escalation, the primary endpoint is incidence and severity of adverse events, including dose limiting toxicities and has been completed. For Stage 2 dose expansion, approximately 120 pts will be enrolled across 4 expansion cohorts. Stage 2 Cohorts 1-3 dose expansion cohorts will enroll pts with previously treated, locally advanced or metastatic NSCLC pts with either EGFR ex20ins mts, HER2 ex20ins mts, or EGFR activating mts, respectively. Cohorts 1-3 allow enrollment of pts with prior EGFR or HER2-directed therapy. Stage 2 Cohort 4 will enroll EGFR TKI-naïve NSCLC pts with EGFR PACC mts. Key inclusion criteria include documented EGFR or HER2 mts by local testing and measurable disease per RECIST v1.1. Stage 2 primary endpoint is ORR using RECIST v1.1. Key secondary endpoints include progression-free survival and overall survival. Stage 2 enrollment is ongoing. 1. Musib et al., NACLC 2022. 2. Robichaux et al., 2021. Clinical trial information: NCT05364073 .

Innovation of the first-line strategy optimized as abemaciclib with endocrine therapy based on the ESR1mutation of ctDNA for patients with HR-positive HER2-negative advanced metastatic breast cancer (JBCRG-M08; AMBER study).

TPS1134 Background: Aromatase inhibitor (AI) + CDK4/6 inhibitor (CDK4/6i) has been established as a standard of care of 1st line treatment for hormone receptor (HR)-positive/HER2-negative advanced metastatic breast cancer (AMBC). ESR1 mutations are considered to be one of the causes of acquiring resistance against the AI +CDK4/6i. PADA-1 trial showed that replacing AI with fulvestrant (FUL) as a partner of palbociclib (PAL) at occurrence of some ESR1 mutations improved progression-free survival (PFS) and PFS2, suggesting PAL should be used based on the strategy of selecting endocrine agents according to ESR1 mutation status by ctDNA analysis. On the other hand, we don’t know if this strategy is effective in the case of abemaciclib (ABM), another CDK4/6i established as the standard of care for AMBC. We are conducting a study to make evidence on this clinical question. Methods: This multicenter, single-arm phase II study is designed to evaluate the efficacy and safety of the strategy to replace AI with FUL for detectable ESR1 mutations in combination with ABM. Key eligibility criteria include patients receiving AI+ABM for at least 6 months as first-line treatment for HR-positive/ HER2-negative AMBC without progressive disease (PD). While continuing AI+ABM, ctDNA analysis will be performed at approximately 3, 9, 15 months from enrollment. If ESR1 mutation is identified at any point and non-PD is confirmed by CT, FUL+ABM will be initiated instead of AI+ABM. In patients with ESR1 mutations completely cleared by ctDNA analysis 6 months after the start of FUL+ABM, AI+ABM will be resumed (Re-AI+ABM arm); the Re-AI+ABM arm is intended to investigate whether the discontinuation of FUL will allow clones with ESR1 mutations to proliferate again. Primary endpoint is 2-year PFS rate in full analysis set. Key secondary endpoints include 2-year PFS rate by treatment sequences, and rate of disappearance of ESR1mutations in ctDNA with FUL+ABM. Plasma-SeqSensei Breast Cancer IVD Kit, which can simultaneously detect mutations in a wide range of six genes including ESR1, as well as PIK3CA, AKT1, ERBB2, KRAS, and TP53, is used for ctDNA analysis in this study. Based on PFS data in MONARCH3 study, the threshold and expected value of the 2-year PFS rate were estimated to be 45% and 55%, respectively, and target sample size was calculated as 160 patients. Patient enrollment started in December 2022 and run through December 2024; as of December 2023, 54 patients have been enrolled. Clinical trial information: 051220133.

Comparison of Cryoballoon vs. Pulsed Field Ablation in Patients with Symptomatic Paroxysmal Atrial Fibrillation (SINGLE SHOT CHAMPION): Study protocol for a randomized controlled trial

IntroductionSingle-shot devices are increasingly used for pulmonary vein isolation (PVI) in atrial fibrillation (AF). The Arctic Front cryoballoon (Medtronic) is the most frequently used single-shot technology. A recently developed novel pulsed-field ablation (PFA) device (FARAPULSE, Boston Scientific) has been introduced with the aim to improve procedural safety and efficacy. ObjectiveThis study will compare the novel FARAPULSE PFA device and the Arctic Front cryoballoon for first PVI in patients with symptomatic paroxysmal AF. MethodsSINGLE SHOT CHAMPION is a multicentre, randomized controlled trial with blinded endpoint adjudication by an independent clinical events committee. Overall, 210 patients with paroxysmal AF undergoing their PVI are randomized 1:1 between PFA and cryoballoon ablation. Continuous rhythm monitoring with an implantable cardiac monitor (ICM) is performed in all patients. ResultsThe primary endpoint is time to first recurrence of any atrial tachyarrhythmia (AF and/or organized atrial tachyarrhythmia) lasting ≥120 seconds and identified by the ICM within 91 and 365 days post-ablation. The composite procedural safety endpoint includes cardiac tamponade requiring drainage, persistent phrenic nerve palsy, vascular complications requiring intervention, stroke/transient ischemic attack, atrioesophageal fistula, and death occurring during or up to 30 days after the procedure. Key secondary endpoints include (1) increase in high-sensitivity Troponin on day 1 post-ablation, (2) analysis of post-ablation 3D electro-anatomical mapping (first 25 patients per study group), (3) AF burden, and (4) quality of life changes ConclusionSINGLE SHOT CHAMPION will evaluate the efficacy and safety of PVI using the novel FARAPULSE PFA for patients with symptomatic paroxysmal AF.

DUET-01: A first-in-human, phase 1/2 study of BOXR1030 in patients with advanced glypican-3-positive solid tumors.

TPS2681 Background: Glypican-3 (GPC3) is a membrane-bound heparin sulfate proteoglycan involved in cell proliferation that is overexpressed in several tumor types. BOXR1030 is an autologous T-cell therapy that co-expresses a chimeric antigen receptor (CAR) targeting GPC3 on tumor cells and glutamic-oxaloacetic transaminase 2 (GOT2), a mitochondrial enzyme that plays an important role in maintaining mitochondrial function and improving T-cell functionality in the solid tumor microenvironment. In non-clinical studies, BOXR1030 showed GPC3-specific cytotoxicity, proliferation and cytokine release only in the presence of GPC3+ cells. Methods: DUET-01 (NCT05120271) is an open-label, dose escalation and expansion clinical trial to determine a safe dose of BOXR1030 in patients with advanced GPC3-positive solid tumors. Dose escalation will be guided by the occurrence of dose-limiting toxicities (DLTs) within 28 days of dosing. The Bayesian logistic regression model will be used on the accumulated DLT data to estimate the maximum tolerated dose (MTD). The Dose Escalation Committee will select the recommended phase 2 dose (RP2D) to be used in the expansion phase cohort(s) (10-20 subjects each) based on data accumulated in the dose escalation cohorts. Eligible subjects will undergo leukapheresis to obtain T cells for BOXR1030 manufacturing and will receive 3 days of lymphodepleting chemotherapy with fludarabine and cyclophosphamide within 5 days prior to BOXR1030 administration. The starting dose is 0.3 × 106 BOXR1030 T cells/kg body weight. Antitumor activity will be assessed every 6 weeks after cell infusion per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 and RECIST for immune-based therapeutics (iRECIST). Six months after BOXR1030 administration, subjects will enter long-term follow-up for up to 15 years. Long-term follow-up assessments will focus on long-term safety and disease status. Main inclusion criteria are histologically confirmed advanced unresectable or metastatic hepatocellular carcinoma, squamous cell carcinoma of the lung, myxoid/round cell liposarcoma, or Merkel cell carcinoma; GPC3 overexpression by immunohistochemistry assay confirmed centrally on tumor specimen taken within 6 months prior to signing consent and after the initiation of the subject’s most recent systemic anticancer therapy; body weight of ≥ 50 kg (≥ 65 kg for dose level 1); and life expectancy > 16 weeks. The primary endpoints are the incidence of DLTs; determination of the MTD and RP2D; the type, frequency and severity of treatment-emergent adverse events; clinically significant abnormal safety laboratory findings and vital signs. Key secondary endpoints include efficacy parameters such as objective response rate, BOXR1030 T-cell expansion and persistence, and levels of inflammatory markers and cytokines. The first patient was treated with BOXR1030 in December 2022. Clinical trial information: NCT05120271 .

Pathologic response rates to neoadjuvant pembrolizumab in locally advanced (LA) resectable cutaneous squamous cell carcinoma (cSCC).

9591 Background: Cutaneous squamous cell carcinoma (cSCC) is the second commonest cutaneous malignancy, accounting for 20% of cutaneous malignancies and 75% of non-melanoma skin cancer deaths. Anti-PD-1 is approved in unresectable and metastatic cSCC, and is associated with high rates of pathologic response in resectable locally advanced (LA) cSCC. We conducted a phase II single-arm neoadjuvant trial of pembrolizumab (P) in patients with PD-1 naïve resectable LA cSCC. Methods: Patients with AJCC/UICC ≥T3 (or T2 with ≥2 BWH high-risk features) and/or N+ disease were eligible. Patients received 2 cycles of P (200mg Q3W) prior to definitive surgery, and 15 cycles post-surgery (NCT04808999). The primary endpoint was pathologic complete response (pCR, defined as 0% residual viable tumor, RVT) per independent central pathology review. Key secondary endpoints included incidence of adverse events (AEs), recurrence-free survival (RFS), overall survival (OS), safety and unbiased spatial biomarkers. A selected panel of multiplex immunofluorescence imaging biomarkers were used by PredxBio Inc.’s computational pipeline to reveal spatial intratumor heterogeneity in the tumor microenvironment (TME). Results: Thirty patients were enrolled and received at least 1 cycle of P. The median age was 79 (59-93) years and patients were predominantly male (77%). One patient withdrew consent prior to surgery. Three patients died prior to definitive surgery: 2 from COVID-19, a third from a NSTEMI possibly related to P. Of the 26 response-evaluable patients, AJCC/UICC stage at baseline was high-risk T2, T3, N1, and N2 in 2 (8%), 12 (46%), 9 (34.5%), and 3 (11.5%) patients, respectively. We observed pCR in 15 (57%), pathologic partial response (pPR, 10% < %RVT <50%) in 2 (8%) and pathologic non-response (pNR, >50%RVT) in 8 (31%) patients. One patient is pending surgery. Postoperative radiotherapy (RT) was de-escalated in 54% of the patients (14/15 in pCR). Median RFS was 13 (pCR) versus 10.5 (non-pCR) months. One Grade 5 (NSTEMI) and two Grade 3 (hepatitis, colitis) treatment-related AEs were observed. Computational analysis identifies key spatial interactions between PDL-1+/CD68+ cells implicated in response to P. Conclusions: Neoadjuvant P is efficacious in resectable LA cSCC with a high pCR rate (57%). Three deaths were observed, including 2 unrelated to treatment and 1 possible Grade 5 cardiac irAE, reflecting the inherent risks of perioperative therapy in this patient population. RT was de-escalated in 93% of pCR patients. No relapse events in pCR patients. Spatial interactions between PDL-1+ cells and CD68+ macrophages have a role in therapeutic response and will be detailed along with other spatial analyses of the TME compartment that have an impact on outcomes. Clinical trial information: NCT04808999 .