28-day Cycle Research Articles

Interim results from a prospective multicenter phase II trial of stratified treatment of localized cervical esophageal squamous cell carcinoma induced by neoadjuvant immunotherapy plus chemotherapy (SCENIC trial).

e16089 Background: Definitive concurrent chemoradiotherapy (dCRT) is the standard treatment for cervical esophageal squamous cell cancer (CESCC). However, salvage esophagectomy poses significant technical challenges in dCRT failures, and optimizing patient selection for dCRT remains an unsolved concern. In this context, we propose a stratified screening strategy by incorporating induction immunochemotherapy, aiming to identify suitable candidates for organ-sparing dCRT and timely surgical treatment. Methods: This prospective multicenter interventional phase II study (ChiCTR2200057732) enrolled patients with clinical stage T2-4NanyM0 (AJCC TNM 8th) resectable CESCC. Eligible participants received induction therapy of intravenous PD-1 inhibitor tislelizumab (200mg, day 1) plus nab-paclitaxel (100 mg/m2, day 1,8,15) and carboplatin (area under curve of 5 mg/mL/min, day 1) of each 21-days cycle, for two cycles. Treatment response was evaluated 4 weeks after the completion of induction therapy, according to the criteria of the CROC trial: Grade 1, remarkable response (RR); Grade 2, limited partial response (LPR); and Grade 3, poor response (POR). Stratified patients would receive different follow-up treatments: dCRT was administered to RR patients, and radical surgery was performed in LPR and POR patients. Tislelizumab was maintained after dCRT in RR patients, and the postoperative adjuvant therapy was dependent on the doctors in the surgery groups. The primary endpoint was the 2-year event-free survival with a planned enrollment of 36 patients in this study. Results: From Jul 2022 to Jan 2024, 28 patients were enrolled. Of these, 22 patients completed the full two-cycle induction therapy and response evaluation. The response after induction immunochemotherapy were RR in 50.0% (11/22), LPR in 31.8% (7/22), and POR in 18.2% (4/22). All of the RR population underwent subsequent dCRT. Among 11 non-RR patients, only 7 cases received esophagectomy, other 4 selected dCRT according to their will. Up to Jan 2024, the median follow-up was 11.0 months (3.5-17.7), all of the RR patients with dCRT were in disease-free survival, 1 LPR and 1 POR patients received dCRT had progression in the primary lesion, and 4 patients underwent surgery had locoregional or distant recurrences. Overall, 24 patients (96%) had any-grade treatment-related adverse events with the most common being leukocytopenia. Four patients (16%) had adverse events of grade 3 or worse, and no treatment-related death occurred. Conclusions: The 1-year survival of RR followed by dCRT appears promising compared to historical data. The strategy of induction immunochemotherapy showed effective in identifying candidates suitable for dCRT in patients with resectable CESCC. Enrollment is ongoing. Clinical trial information: ChiCTR2200057732.

Possibilities of long-term atezolizumab immunotherapy in patients with metastatic urothelial cancer.

e14628 Background: Results from various studies have indicated that atezolizumab can be an effective and well-tolerated treatment option for patients with advanced and metastatic urothelial cancer. However, the landscape of oncological practices in Uzbekistan reflects a scarcity of experience and data concerning the utilization of atezolizumab in the treatment of patients afflicted with urothelial cancer. This research endeavors to bridge this gap by contributing. Methods: In our retrospective study, a total of 44 patients were selected, with a mean age of 64.5±7.6 years, diagnosed with stage IV urothelial cancer and the presence of distant metastases in the lungs, bones, and liver. There were 28 (63.6%) males and 16 (36.4%) females. Group 1 included 18 (40.9%) patients with elevated PD-L1 levels SP142 – IC 2/3, receiving atezolizumab at 1200 mg intravenously (IV) on day 1 of each 21-day cycle + cisplatin at a dose of 70 mg/m2 body surface area (BSA), IV, on day 1 of each cycle, and gemcitabine at a dose of 1000 mg/m2 BSA, IV, on days 1 and 8 of each cycle. Group 2 included 26 (59.1%) patients receiving standard chemotherapy (cisplatin + gemcitabine) in the same regimens. Immunohistochemical analysis was performed using the Ventana Bench Mark Ultra automated stainer with Ventana PD-L1 SP142 monoclonal antibodies. Results: The research was conducted from September 2019 to May 2023, and the administered treatment was the first line for these patients. Treatment was administered until disease progression was registered or until the development of unacceptable toxicity. Grade I toxicity was not observed in both groups. Grade II toxicity in Group 1 was noted in 3 (16.7%), and in Group 2 - in 4 (15.4%). Grade III toxicity was identified in 9 patients (50.0%) in Group 1 and 14 patients (53.8%) in Group 2. Grade IV toxicity was encountered in 6 patients (33.3%) in Group 1 and 8 patients (30.8%) in Group 2. Hematological toxicity, regardless of atezolizumab use, predominated among the III and IV degrees of toxicity. The median overall survival in Group 1 was 14.8 months (95% CI: 12.8-16.2), while in Group 2, it was 11.9 months (95% CI: 9.3-13.5). Progression-free survival in Group 1 was 6.8 months (95% CI: 5.1-7.4), and in Group 2, it was 4.3 months (95% CI: 3.8-5.7). The objective response rate in Group 1 was 44.5%, and in Group 2, it was 38.5%. Conclusions: Atezolizumab, used in combination with standard platinum-based chemotherapy in the first line, improves treatment outcomes for metastatic urothelial cancer by increasing overall survival and progression-free survival without causing an increase in the toxicity of the administered therapy.

Preliminary experience of ex-vivo expanded allogeneic universal donor TGFβi NK cell infusions in combination with irinotecan, temozolomide, and dinutuximab in patients with relapsed or refractory neuroblastoma: The Allo - STING trial.

10005 Background: Neuroblastoma (NBL) is the most common extra-cranial solid tumor in children and outcomes for children with relapsed/refractory (RR) NBL remain dismal. While the combination of chemoimmunotherapy (CIT) with the anti-GD2 antibody dinutuximab as per COG protocol ANBL1221 has improved responses, this regimen is still not curative. Dinutuximab can recruit NK cells for anticancer activity, however, NK cells are depleted in NBL patients undergoing chemotherapy. We devised a method to expand allogeneic NK cells ex vivo to improve effector function and render the NK cells resistant to TGFβ-induced suppression (TGFβi). These TGFβi NK cells are expanded from a universal donor (UD) pool, enabling multiple cycles of “off-the-shelf” high-dose therapy. We hypothesize that adoptive transfer of UD-TGFβi NK cells to patients with RR NBL sequentially following CIT is safe and improves outcomes compared to CIT alone. Methods: This Phase I/II study evaluates the safety and tolerability of UD-TGFβi NK cells in combination with CIT and compares anti-cancer efficacy to CIT alone. Eligibility includes age < 30 years, RR or progressive NBL, and prior treatment with at least 4 cycles of induction chemotherapy. The treatment protocol consists of 21-day cycles of CIT as per COG protocol ANBL1221 with UD-TGFβi NK cells (1x108 cells/kg) infused on day 8. Up to six cycles of treatment are permitted. Overall response rates are defined using the Revised International NBL Response Criteria, with 95% confidence intervals compared to the results from ANBL1221. Progression-free and overall survival will be estimated by the Kaplan Meier method. Results: Four subjects (7 – 11 years) have been enrolled. All patients presented with high risk NBL: three with relapsed disease and one with refractory disease. All received at least one prior salvage therapy. Three patients have completed all 6 cycles of protocol therapy, and one remains on treatment. 20 NK cell infusions have been administered to date. All NK cell infusions occurred within the protocol specified window. One subject experienced grade 1 fever with two NK cell infusions. There have been no other adverse events attributable to the NK cells. Adverse events attributable to CIT were similar to those described in COG ANBL 1221. Treatment delays for cytopenias due to CIT occurred in two patients. Three patients achieved a partial response. A fourth patient attained prolonged stable disease (9 months) but experienced a skeletal recurrence. Conclusions: UD allo-TGFβi NK cells can be safely and feasibly administered to children with RR NBL after treatment with CIT, with early objective responses observed in the preliminary cohort of patients. Ongoing studies will assess markers of response, NK cell persistence, pharmacokinetics and pharmacodynamics. Clinical trial information: NCT04211675 .

Health-related quality of life (HRQoL) results for adjuvant alectinib vs chemotherapy in patients with resected ALK+ non-small cell lung cancer (NSCLC): Data from ALINA.

8006 Background: ALINA (NCT03456076) is a global, open-label, phase 3, randomized trial evaluating the efficacy and safety of adjuvant alectinib versus chemotherapy in patients with resected stage IB (≥4 cm)–IIIA, ALK+ NSCLC. A significant disease-free survival benefit was observed with alectinib vs chemotherapy (HR 0.24, 95% CI: 0.13–0.43, p<0.0001; N=257 patients in the ITT). In the adjuvant setting, where patients have received surgery with curative intent, the impact of treatment on HRQoL is an important clinical consideration. We report HRQoL results from ALINA. Methods: Patients ≥18 years old with ECOG PS 0/1 and completely resected, stage IB–IIIA, ALK+ NSCLC (UICC/AJCC 7th edition) were randomized 1:1 to receive oral 600 mg alectinib twice-daily for 2 years, or four 21-day cycles of platinum-based chemotherapy. HRQoL was an exploratory endpoint measured using the Short Form-36 version 2 (SF-36v2) health survey, which assesses functional health and well-being across 8 domains and 2 aggregated summary scores: the physical (PCS) and mental (MCS) component summary scores. Patients completed the SF-36v2 at baseline, every 3 weeks to Week 12, then every 12 weeks until disease recurrence, withdrawal of consent, death, or Week 96 (or equivalent post-chemotherapy follow-up visit). SF-36v2 was scored using norm-based scoring relative to the 2009 US general population (mean ± standard deviation: 50 ± 10), with higher scores indicating better health. Within-group minimal important differences (MIDs) were used as benchmarks for each domain, MCS and PCS. Data cut-off: 26 June 2023. Results: Completion rates were generally high (>90%) throughout the study. At baseline, most mean scores were low (<50) and were similar between study arms. With alectinib, mean scores were ≥50 for the Bodily Pain, Mental Health and Vitality domains by Week 96, suggesting that patients functioned as well as the general population on these aspects. The mean change from baseline met or exceeded MIDs for 5 domains and MCS by Week 12, and exceeded MIDs for 6 domains, MCS and PCS by Week 96. In the chemotherapy arm, mean scores were low during treatment; mean change from baseline for General Health and Vitality exceeded negative MIDs, indicating worsening in these domains. Mean scores improved in the post-chemotherapy period; in the final assessment, mean scores were ≥50 for the Bodily Pain, Mental Health and Vitality domains, and MIDs were met or exceeded for MCS, PCS and 5 domains. Conclusions: Alectinib demonstrated an improvement in most domains of HRQoL by Week 12, followed by maintenance of HRQoL on all 8 domains, MCS and PCS to Week 96. With chemotherapy, HRQoL was low during treatment, but improved in the post-chemotherapy period. Together with the DFS benefit seen in ALINA, these data support alectinib as an important new adjuvant treatment for patients with resected ALK+ NSCLC. Clinical trial information: NCT03456076 .

Sacituzumab govitecan (SG) + pembrolizumab (pembro) in first-line (1L) metastatic non-small cell lung cancer (mNSCLC) with PD-L1 ≥ 50%: Cohort A of EVOKE-02.

8592 Background: SG, a Trop-2–directed antibody-drug conjugate, has clinical activity and manageable safety in heavily pretreated patients with mNSCLC. EVOKE-02 (NCT05186974) is an ongoing, global, open-label, multicohort phase 2 study evaluating SG + pembro ± platinum agent as 1L treatment for mNSCLC. We report safety and efficacy results from Cohort A of EVOKE-02, with a median follow-up of 11.3 months. Methods: Patients aged ≥18 years with no prior systemic mNSCLC treatment, no actionable genomic alterations, and an ECOG performance status of 0 or 1 were enrolled into Cohort A [PD-(L)1 tumor proportion score ≥50%, 22C3 assay]. Patients received SG 10 mg/kg intravenously on days 1 and 8 + pembro 200 mg intravenously on day 1 of 21-day cycles. Primary endpoints include objective response rate (ORR; RECIST v1.1) per independent review committee (IRC); secondary endpoints include progression-free survival (PFS), duration of response (DOR), disease control rate (all per IRC), overall survival (OS), and safety. Results: As of December 1, 2023, 30 patients in Cohort A were enrolled and had received SG + pembro. Median age was 67 (range, 47-77) years; 60% had nonsquamous histology and 80% had an ECOG performance status of 1. Among all treated patients (n=30), ORR was 67% (95% CI, 47-83%) (squamous, 67% [95% CI, 35-90%]; nonsquamous, 67% [95% CI, 41-87%]). Median PFS was 13.1 (95% CI, 5.5-not reached [NR]) months (squamous, NR [95% CI, 1.2-NR] months; nonsquamous, 13.1 [95% CI, 5.5-NR] months). Median DOR was NR. In the safety population (n=30), the incidence of grade ≥3 treatment-emergent adverse events (TEAEs) and of grade ≥3 TEAEs related to any study drug were 67% and 40%, respectively. Grade ≥3 TEAEs in ≥10% of patients were neutropenia (17%), diarrhea (10%), and respiratory failure (10%). TEAEs leading to SG discontinuation occurred in 17%. There was 1 (3%) treatment-related death due to neutropenic sepsis. Conclusions: SG + pembro demonstrated promising activity in patients with tumor proportion score ≥50% mNSCLC. AEs were manageable and consistent with the known safety profile of each individual agent. The EVOKE-03 study (NCT05609968) of pembro vs SG + pembro in mNSCLC is ongoing. Clinical trial information: NCT05186974 . [Table: see text]

First-in-human trial of M9140, an anti-CEACAM5 antibody drug conjugate (ADC) with exatecan payload, in patients (pts) with metastatic colorectal cancer (mCRC).

3000 Background: CEACAM5 is a cell surface protein with limited expression in adult healthy tissues, but high expression in various adenocarcinomas, particularly in CRC (>90% of pts). M9140 is the first anti-CEACAM5 ADC with a topoisomerase 1 inhibitor (Top1i) payload (exatecan). The ß-glucuronide linker connecting the M9140 antibody backbone to the payload is highly stable in circulation (drug-to-antibody ratio=8). In preclinical models, M9140 has demonstrated strong potency, antitumor activity, and a bystander effect. Methods: This Phase 1 trial (NCT05464030) investigated the safety, tolerability, pharmacokinetics (PK), and preliminary clinical activity of M9140 as monotherapy (Q3W [Day 1 of 21-day cycles]; IV) in adults with CRC (ECOG PS ≤1) who had received ≥2 prior lines of treatment. The primary objectives of Part 1A were to determine the maximum tolerated dose (MTD) and/or recommended dose(s) for expansion (RDE). Results: At data cutoff (19 Jan 2024), 40 pts from the US, EU, and Japan were treated across 7 dose levels (DLs): 0.6 mg/kg, 1.2 mg/kg (n=3, each), 2.4 mg/kg (n=7), 2.6 mg/kg (n=4), 2.8 mg/kg (n=12), 3.0 mg/kg (n=4), and 3.2 mg/kg (n=7, including 3 pts with primary G-CSF prophylaxis). Most pts were heavily pretreated (80% had ≥3 lines of prior treatment; 100% received irinotecan). Overall, 6 pts experienced dose-limiting toxicities (DLTs); the majority were hematological adverse events at DLs 3.0 and 3.2 mg/kg; 1 patient (at 2.8 mg/kg) experienced a Grade 5 sepsis. The most frequently reported Grade ≥3 treatment-emergent adverse events (TEAEs) were neutropenia in 16 (40.0%) pts, thrombocytopenia and anemia in 11 (27.5%) pts each, and WBC decreased in 10 (25.0%) pts. No events of ocular toxicity/interstitial lung disease (ILD) were reported. The best objective response per RECIST v1.1 was partial response (PR) in 4 (10.0%) pts (3 confirmed) (all at DLs ≥2.4 mg/kg); stable disease (SD) in 17 (42.5%), including 6 (15.0%) lasting for ≥100 days and progressive disease (PD) in 6 (15.0%) pts. For a total of 13 (32.5%) pts, the best overall response was not evaluable, including 6 (15.0%) who had no on-treatment tumor assessment yet. The preliminary median progression-free survival (PFS) was 6.7 months (95% CI: 4.6, 8.4). As of data cutoff, 15 (37.5%) pts are continuing treatment. Based on the safety, tolerability, preliminary clinical activity, PK, and PK/pharmacodynamics modeling data, 2.8 mg/kg was declared as the MTD, and 2.4 mg/kg and 2.8 mg/kg were chosen as the RDEs and have been taken forward into a randomized expansion study. Conclusions: M9140 demonstrated encouraging activity in heavily pretreated pts with advanced CRC, with a manageable and predictable safety profile. Contrary to approved ADCs with Top1i payloads, no ILD or ocular toxicities were observed. Evaluation of M9140 in mCRC continues in the dose expansion part of this study. Clinical trial information: NCT05464030 .

A phase 2 study of ipatasertib in combination with pembrolizumab for first-line treatment of recurrent or metastatic squamous cell cancer of the head and neck.

TPS6117 Background: Single agent pembrolizumab in relapsed / metastatic head and neck squamous cell carcinoma (R/M HNSCC) has an estimated ORR of 19% and median OS of 13.6 months. There are several factors which may influence which patients respond to antibodies targeting the PD-1 axis. Regulatory T cells (Tregs) play a significant role in an immunosuppressive tumor microenvironment. Anti-PD-1 antibodies induce Treg activation in part through AKT pathway activation, which may contribute to low response rates to checkpoint inhibitor therapy. AKT blockade selectively inhibits the proliferation of human Tregs. Additionally, inhibition of the PI3K-AKT-mTOR pathway limits myeloid-derived suppressor cells (MDSC) infiltration and differentiation, and boosts CD8+ T cell memory and effector function. Ipatasertib is an oral highly selective small-molecule inhibitor of all three isoforms of AKT. This phase 2 trial is designed to compare progression-free survival (PFS) in first line R/M, HNSCC patients treated with the combination ipatasertib and pembrolizumab versus pembrolizumab monotherapy treatment. Methods: In this open-label randomized phase 2 multicenter trial, patients with R/M HNSCC are treated with pembrolizumab 200mg on day 1 +/- ipatasertib 400mg QD days 1-14 of 21-day cycles. Patients must have PD-L1 CPS score ³ 1, have measurable disease per RECIST 1.1, and consent to on-treatment biopsy. Patients will be excluded if they have received prior systemic therapy for R/M HNSCC, cannot swallow a pill, or require insulin for diabetes. The primary objective is to compare the PFS between the two arms. We will estimate the relative hazard ratio associated with ipatasertib plus pembrolizumab compared to pembrolizumab alone using the Cox Model where randomized treatment assignment is the only variable in the model. Secondary objectives include ORR, safety and tolerability of the combination, and changes in tumor immune cell infiltration, AKT signaling, and changes in peripheral blood immune cells. Ultimately, a total of 48 patients will be enrolled, with 24 patients in each cohort. To date, a total of 22 patients have been enrolled from 15 sites. Accrual is ongoing (NCT05172258). Clinical trial information: NCT05172258 .

Three-year survival data from a phase 2 trial of neoadjuvant short-course radiotherapy followed by chemotherapy and camrelizumab in locally advanced rectal cancer.

e15611 Background: For locally advanced rectal cancer (LARC), short-course radiotherapy (SCRT) or long-course chemoradiotherapy combined with chemotherapy have been the established neoadjuvant treatment, but the optimal therapeutic modality is still under exploration. We previously reported the short-term results of neoadjuvant SCRT followed by chemotherapy and camrelizumab (a PD-1 inhibitor), encouragingly noting pathological complete response (pCR) in 48.1% of LARC patients (Lin Z et al. J Immunother Cancer 2021;9:e003554). Here, we report the further 3-year follow-up results. Methods: Adult patients with histologically confirmed T3-4N0M0 or T1-4N+M0 rectal adenocarcinoma were enrolled. Prior to surgery, eligible patients received 5×5 Gy SCRT, and after one week, they were treated with camrelizumab (200 mg, i.v., on day 1) plus CAPOX chemotherapy (oxaliplatin 130 mg/m2, i.v., on day 1 and capecitabine 1000 mg/m2, orally, bid, on days 1-14) in 21-day cycles for 2 cycles. Radical surgery was performed one week after the last neoadjuvant cycle. For this updated analysis, disease-free survival (DFS) and overall survival (OS) at 3 years are reported. Results: Thirty patients were enrolled and received SCRT, and all of these patients were included in this OS analysis. Among them, 27 patients received camrelizumab plus CAPOX chemotherapy, all of whom underwent surgery and were included in this DFS analysis. Of the 27 patients, 21 patients (77.8%) received at least one cycle of postoperative adjuvant chemotherapy with CAPOX regimen. With a median follow-up of 40.8 months (IQR 40.3-44.3), disease recurrence or death occurred in six (22.2%) patients. The median DFS and OS were both not reached, with the 3-year DFS and OS rates of 80.2% (95% CI 58.6-91.3) and 93.3% (95% CI 75.9-98.3), respectively. Subgroup analysis showed that patients with pCR, postoperative pathological node-negative status, PD-L1 combined positive score ≥ 1, and negative circumferential resection margin and negative extramural venous invasion by MRI at baseline had a tendency towards improved 3-year DFS and OS compared to those without these characteristics. No new or long-term safety signals were identified. Conclusions: With 3 years of extended follow-up, a favorable survival benefit was observed with neoadjuvant SCRT combined with subsequent CAPOX plus camrelizumab followed by delayed surgery in LARC patients. A randomized phase 3 trial (NCT04928807) is ongoing to confirm these results. Clinical trial information: NCT04231552 .

Phase I/II safety and preliminary efficacy of PM1022, a bispecific antibody targeting PD-L1 and TIGIT, in patients with advanced solid tumors.

e14694 Background: PM1022 is an anti-PD-L1 × TIGIT bispecific antibody that is engineered with a fully human IgG targeting TIGIT in an IgG1 wild type Fc backbone, fused to a VHH at the c-terminus targeting PD-L1. The potential MOA includes releasing T cell inhibition by blocking both the PD-L1/PD-1 and CD155/CD112/TIGIT pathways, as well as depleting Treg cells in the tumor microenvironment and engaging FcγRs to activate myeloid cells. PM1022 showed robust in vitro and in vivo efficacy in preclinical studies, and this is the first in human study. Methods: This phase Ⅰ/Ⅱ study consists of a standard 3+3 dose escalation and dose expansion part. PM1022 was administered intravenously as monotherapy on Day 1 of 21-day cycle. The primary objectives were to assess safety, tolerability and pharmacokinetics in patients with advanced solid tumors. Results: As of January 28, 2024, a total of 15 patients in dose escalation part have received at least 1 dose of PM1022, with 3 patients in each of the 100, 200, 400, 800 and 1200 mg dose levels respectively. No DLT was observed up to 1200 mg. Of the 15 patients, TRAEs occurred in 8 patients (53.3%), ≥ Grade 3 TRAEs occurred in 1 patient with platelet count decreased. No patients were discontinued from PM1022 due to TRAE. The most common TRAEs were rash (20%) and aspartate transaminase increased (20%). 14 patients completed at least one tumor evaluation. The median duration of PM1022 exposure was 6.1 weeks (range, 5.0-48.0 weeks). The ORR per RECIST 1.1 was 7.1% with a DCR of 35.7%. Preliminary antitumor activity has been observed in 1 patient with NSCLC (1200 mg, still on treatment) with previous PD-L1 TPS 100% who was enrolled after previous 3 lines therapy, including chemotherapy and anti-PD-1 treatment, and had a partial response in target lesion with 56.8% reduction. Another patient with esophageal cancer had been on PM1022 for total of 48 weeks until initiation of new anti-cancer therapy. Pharmacokinetics were dose-proportional with a terminal half-life of 7-13 days across the dose range of 100-1200 mg. Conclusions: PM1022 was safe and well-tolerated up to 1200 mg Q3W with preliminary anti-tumor activity. These findings could support further exploration of PM1022 in advanced solid tumors. Clinical trial information: NCT05867771 .

A phase 1/2, first-in-human study of DS-3939a in patients with advanced solid tumors: A new DXd ADC targeting TA-MUC1.

TPS3165 Background: Mucin 1 (MUC1), a single-transmembrane glycoprotein, is expressed on the apical membrane of the epithelial surface. In normal tissues, it is highly glycosylated and protects the underlying epithelia. In cancer cells, however, MUC1 is hypoglycosylated due to changes in the expression patterns of some sialyltransferases, and exposes new epitopes on MUC1 in tumors, referred to as tumor-associated MUC1 (TA-MUC1). TA-MUC1 loses cell polarity and is redistributed over the cell surface and within the cytoplasm. Overexpression of TA-MUC1 in several malignancies is associated with poor prognosis and development of metastasis, thus making it an attractive therapeutic target. DS-3939a is a novel antibody-drug conjugate in development for the treatment of malignant tumors composed of a humanized anti-TA-MUC1 antibody, a peptide-based cleavable linker, and a potent topoisomerase I inhibitor (DXd). This study will assess the safety, tolerability, and efficacy of DS-3939a in patients with advanced solid tumors. Methods: This phase 1/2, first-in-human, open-label, multicenter, 2-part, dose-escalation, and dose-expansion study (NCT05875168) is active and plans to enroll up to 430 adult patients. Part 1 (dose-escalation) is accruing patients with locally advanced, metastatic, or unresectable urothelial, non-small cell lung, breast, ovarian, biliary tract, or pancreatic cancers, and Part 2 (dose-expansion) will enroll patients with various advanced solid TA-MUC1-expressing tumors. In Parts 1 and 2, DS-3939a will be administered intravenously on Day 1 of a 21-day cycle. The primary endpoints in Parts 1 and 2 include safety and tolerability of DS-3939a as assessed by the number of patients with dose-limiting toxicities (Part 1 only), treatment-emergent adverse events, and other safety parameters. Part 2 will also evaluate efficacy by objective tumor response rate per RECIST version 1.1 as a primary endpoint. Secondary endpoints include the disease control rate, duration of response, time to response, progression-free survival, overall survival, TA-MUC1 expression (detected by immunohistochemistry), the pharmacokinetic profile of DS-3939a, and the number of patients with anti-drug antibodies against DS-3939a. Clinical trial information: NCT05875168 .

A phase 2a safety run-in and preliminary efficacy study of liposomal gemcitabine (FF-10832) in combination with pembrolizumab in patients with advanced solid tumors.

2615 Background: FF-10832 (FF832) [liposomal gemcitabine (GEM)] has demonstrated superior activity preclinically compared to GEM via preferential tumor accumulation & induction of antitumor immune responses. Further enhanced activity has been shown in combination with immune checkpoint inhibitors. We evaluated the tolerability & preliminary efficacy of FF832 in combination with the PD-1 antibody pembrolizumab (PEM) in a Phase 2a safety run-in study in patients (pts) with advanced solid tumors. Methods: Pts received 200 mg PEM followed by 40 mg/m2 FF832 on Day 1 of a 21-day cycle to validate the recommended Phase 2 dose (RP2D) for combination therapy; treatment was continued until disease progression or unacceptable toxicity. Response was assessed by RECIST 1.1 every 2 cycles. Tumor PD-L1 expression, mutational burden, and modulation of circulating immune cells were assessed, & population PK modeling performed. Results: Twelve pts [NSCLC (6), urothelial cancer, UC (4), renal cell carcinoma (2); 6M/6F; median age, 69 (42-82) & median # prior therapies, 5 (1-7); prior GEM (5), prior PEM (9)] received a median of 2 (1-8) cycles FF832+PEM. Median time on study was 6.1 (1.1–23.7) weeks. FF832+PEM was well-tolerated. Common AEs related to FF832 were Gr≤2 fatigue (50%) with 1 Gr 3, anemia (33%) with 2 Gr 3, & Gr ≤2 decreased appetite, diarrhea, ↑AST, ↑AlkPhos, muscular weakness, nausea, and pyrexia (25% each). Common AEs related to FF832+PEM were Gr≤2 fatigue (33%) & nausea (25%). Three pts had Gr≤2 infusion reactions with the first FF832 infusion; all resolved & were successfully rechallenged. FF832 dose was reduced to 30 mg/m2 after Cycle 1 in 3 pts due to Gr 3 rash (1), Gr 2 fatigue (1), & one DLT of Gr 3 malaise, pain, and arthralgia. Of 9 pts evaluable for response, one achieved an unconfirmed PR after one cycle (UC, prior GEM/PEM, 42%↓ in target lesions). Five pts had a best response of SD with 2 maintained for 6-8 cycles. Median PFS was 6 weeks (95%CI: 3.1–NR); median OS was 23.3 weeks (95%CI: 4–NR). An extended plasma t1/2 (~30 hours) & exposures consistent with FF832 monotherapy at the RP2D were observed. As with FF832 monotherapy, multi-log decreases were observed in circulating Ki67+ Tregs relative to total CD4+ cells while CD8+ cells increased, suggesting FF832+PEM could enhance shifts to a more immunocompetent tumor microenvironment. Conclusions: The safety and preliminary efficacy of FF832+PEM was demonstrated in heavily pre-treated pts with solid tumors whose disease progressed on prior GEM and/or PEM. Continuous GEM exposure from FF832 along with immune checkpoint blockade may improve antitumor activity. Evaluation of FF832 at the RP2D/schedule of 40 m/gm2 Q 21 days alone and in combination with PEM is ongoing in a randomized expansion study in pts with metastatic NSCLC and UC with prior disease progression on PD-1/L1 therapy. Clinical trial information: NCT05318573 .

Efficacy, safety, and predictive biomarkers of dalpiciclib combined with letrozole, pertuzumab and trastuzumab as neoadjuvant therapy in HR+/HER2+ breast cancer: A phase II study.

e12621 Background: HR+/HER2+ breast cancer is a unique subtype of breast cancer. Between ER and HER2 crosstalk pathways may affect the sensitivity to both HER2-targeted and endocrine therapy in patients with HR+/HER2+ breast cancer. Current therapies for HER2-positive breast cancer have demonstrated limited efficacy in patients with HR+/HER2+ breast cancer. This Phase II trial aimed to assess the efficacy and safety of a neoadjuvant regimen combining trastuzumab, pertuzumab, dalpiciclib (a cyclin dependent kinase 4/6 inhibitor) and letrozole in patients with HR+/HER2+ breast cancer, alongside the exploration of efficacy biomarkers. Methods: Patients were administered six 28-day cycles of dalpiciclib (150 mg once daily on days 1-21) and letrozole (2.5 mg once daily), plus six 21-day cycles of trastuzumab (8 mg/kg loading dose followed by 6 mg/kg maintenance dose on day 1), pertuzumab (840mg loading dose followed by 420mg maintenance dose on day 1), prior to surgery. The primary endpoint was total pathological complete response (tpCR, ypT0/is, ypN0) rate. Secondary endpoints were objective response rate (ORR), breast pathological complete response (bpCR; ypT0/is) rate, change in Ki-67 level from baseline to one cycle of treatment and to surgery, and safety. For biomarkers analysis, next-generation sequencing was performed on pre-treatment tissue and circulating tumor DNA (ctDNA) at various time points before surgery. Results: A total of 14 patients who completed the neoadjuvant treatment and surgery between July 12, 2022 and August 12, 2023 were enrolled. A 50.0% (7 out of 14) tpCR and bpCR rate was observed, with an ORR of 92.9%. Significant reductions in Ki-67 levels were noted after both one ( P<0.05) and six cycles of neoadjuvant therapy ( P<0.05). Grade 4 neutropenia was reported in one case, with no fatalities. The most common grade 3 adverse events were neutropenia (10 [71.4%]) and leukopenia (8 [57.1%]). NGS identified frequent mutations in TP53 (84.6%), PIK3CA (53.8%), and ARID1A (30.8%). Cell cycle pathway gene alterations correlated with a higher pCR rate (80% vs 25%, P=0.103). Eight (61.5%) patients had positive ctDNA at baseline, and ctDNA positivity decreased significantly post-neoadjuvant treatment ( P<0.05). Patients with positive ctDNA at baseline without clearance post-treatment exhibited a trend towards a lower pCR rate. Conclusions: This combination neoadjuvant regimen of dalpiciclib, letrozole, pertuzumab and trastuzumab demonstrated promising pathological responses and manageable safety in patients with HR+/HER2+ breast cancer. The predictive value of genetic alterations and ctDNA status for treatment efficacy warrants further investigation. Clinical trial information: ChiCTR2200062114.

Efficacy and safety of mecapegfilgrastim in preventing neutropenia during concurrent chemoradiotherapy.

e24119 Background: Current guidelines recommend prophylactic use of granulocyte colony-stimulating factor (G-CSF) to reduce the incidence, duration, and severity of chemotherapy-induced neutropenia. We evaluated the efficacy and safety of mecapegfilgrastim, a long-acting G-CSF, in preventing neutropenia for solid tumor patients during concurrent chemoradiotherapy (CCRT). Methods: In this multicenter, open-label, randomized controlled trial, patients with lung, esophageal, or cervical cancers, and an ECOG performance status of 0-2 were randomized 1:1 to the study or control group. Both groups received standard CCRT with two 21-day cycles of taxanes and platinum-based chemotherapy. In the study group, mecapegfilgrastim 6 mg was administered 24 hours after chemotherapy for each cycle, whereas the control group received no prophylaxis for neutropenia. Short-acting G-CSF was administered if neutrophil counts fell below 2.0×10^9/L. Treatment-emergent adverse events (TEAEs) were monitored for 2 cycles and graded per CTCAE v5.0. The primary endpoint was the incidence of grade 3/4 neutropenia during CCRT. Results: From Apr 2022 to Dec 2023, 97 patients were enrolled: 48 in the study group and 49 in the control group. The median age was 59 years (range 51-71) in the study group and 60 years (range 34-71) in the control group. Baseline characteristics were balanced between two groups. Eleven patients (22.9%) in the study group experienced grade 3/4 neutropenia, compared to 27 (55.1%) in the control group (nominal p= 0.002). Three patients (6.3%) in the study group and 2 (4.1%) in the control group developed febrile neutropenia (FN). For 18 lung cancer patients, none of the study group experienced grade 3/4 neutropenia, while 2 patients (25.0%) in the control group did. FN was not reported in either group. Among 40 esophageal cancer patients , grade 3/4 neutropenia was observed in 4 patients (21.1%) of the study group, compared to 12 (57.1%) of the control group, with one case of FN in each group. For 39 gynecological cancer patients, grade 3/4 neutropenia occurred in 7 patients (36.8%) in the study group and 13 (65.0%) in the control group. Two patients of the study group and 1 of the control group developed FN. Short-acting G-CSF was required in 18 patients (37.5%) of the study group and 33 (67.4%) of the control group. TEAEs were reported in 27 patients (56.3%) of the study group and 41 (83.7%) of the control group. Notably, grade ≥3 TEAEs were reported in 21 patients (43.8%) of the study group and 30 (61.2%) of the control group, maily including hematologic toxicities like neutropenia, thrombocytopenia, and lymphocytopenia. Serious TEAEs were reported in 1 patient (2.1%) of the study group and 2 (4.1%) of the control group. One patient (2.1%) in the study group discontinued treatment due to TEAEs. Conclusions: Prophylaxis with mecapegfilgrastim reduced the incidence of grade 3/4 neutropenia during CCRT, with good safety. Clinical trial information: ChiCTR2200058551.

LUNAR-2: Pivotal, randomized, open-label study of tumor treating fields (TTFields, 150 kHz) concomitant with pembrolizumab and platinum based chemotherapy for the treatment of metastatic non-small cell lung cancer.

TPS8665 Background: Tumor Treating Fields (TTFields) are electric fields that disrupt processes critical for cancer cell viability. TTFields are delivered by a noninvasive portable device that has the European CE Mark and FDA approval for glioblastoma and mesothelioma. Preclinical non-small cell lung cancer (NSCLC) studies demonstrated that TTFields enhance the antitumor immune response, through disruption of mitosis and subsequent induction of immunogenic cell death. The pivotal, phase III LUNAR study (NCT02973789) in metastatic NSCLC progressing on/after platinum-based therapy demonstrated that TTFields with an immune checkpoint inhibitor (ICI) or docetaxel provided a statistically significant and clinically meaningful 3.3-month improvement in median overall survival (OS) vs an ICI or docetaxel alone, with no added systemic toxicities and no clinically significant difference on quality of life between groups. Despite advances in the treatment of NSCLC, survival rates for stage IV disease remain poor and there is a need for effective and tolerable treatments. Methods: LUNAR-2 (NCT06216301) is a pivotal, global, randomized, trial investigating the efficacy and safety of TTFields concomitant with pembrolizumab (P) and platinum-based chemotherapy (C) in patients (pts) with metastatic NSCLC, with a planned enrollment of 734 pts at 134 sites. Pts with NSCLC, radiologically evaluable disease in the thorax, ECOG PS of 0–1, and no prior treatment for metastatic disease are eligible. Pts will be stratified by histology, PD-L1 Tumor Proportion Score (TPS) and prior treatment with immunotherapy. Randomization is 1:1 to TTFields/P+C or P+C alone. Standard doses of P+C will be administered to both arms on day 1 of a 21-day cycle for 4 cycles of induction followed by up to 31 cycles of maintenance with TTFields/P or P alone. TTFields generated by the NovoTTF-200T System, will be delivered to the thorax ≥ 18 h/day until local disease progression per iRECIST. The primary endpoints are OS and progression-free survival (PFS) per RECIST v1.1 as assessed by a blinded independent central review (BICR). Secondary endpoints include OS and PFS according to histology or PD-L1 TPS, objective response rate, duration of response, and disease control rate, all per RECIST v1.1 as assessed by BICR and by investigator, comparing TTFields/P+C vs. P+C alone. Other secondary endpoints include PFS rates at 6, 12, 24 and 36 months per RECIST v1.1 as assessed by BICR, 1-, 2-, and 3-year survival rates and safety. Device Support Specialists will provide technical and lifestyle integration training for pts and caregivers throughout TTFields therapy. Pts usage is tracked by the device and is provided to pts and physicians to facilitate discussions to optimize outcomes by maximizing time on therapy. The trial is currently recruiting. Clinical trial information: NCT06216301 .

Ipatasertib (IPA) combined with non-taxane chemotherapy (CT) for patients (pts) with previously treated advanced triple-negative breast cancer (aTNBC): The PATHFINDER phase IIa trial.

1098 Background: New therapies are urgently needed for aTNBC. The PI3K/AKT/mTOR pathway and its link to chemoresistance warrant further investigation in pre-treated TNBC patients. The pan-AKT inhibitor IPA, alone or combined, has shown promise for treating advanced solid tumors. This study assessed the toxicity and efficacy of IPA with non-taxane CT in aTNBC pts. Methods: PATHFINDER (NCT04464174) is a multicenter, open-label, non-comparative, phase IIa trial with a safety run-in phase. Taxane-pretreated aTNBC pts with 1-2 prior CT lines for advanced disease and ECOG 0-1 were eligible. Based on prior treatment and available slots, pts received 21-day cycles of IPA (oral, 400 mg/d for 14 d) either with capecitabine (CA) (oral, 2 g/m2/d for 14 d) (arm A); eribulin (E) (IV, 1.23 mg/m2 on d1 and d8) (arm B); or carboplatin plus gemcitabine (CG) (IV, AUC 5 on d1 and 1000 mg/m2 on d1 and d8, respectively) (arm C) until disease progression (PD) or unacceptable toxicity. Initially, the safety run-in phase included 3 pts/arm to determine phase IIa doses based on the toxicity observed after 2 cycles. The primary endpoint was incidence of adverse events (AEs) as per NCI-CTCAE v.5.0. Key secondary endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Analysis was exploratory with no hypothesis testing. Results: From September 2020 to October 2022, 54 pts were assigned to arms A (n = 22), B (n = 25), and C (n = 7). In arm C, 4 additional pts received a lower dose level of IPA (300 mg/d) in the safety run-in phase. Based on the toxicity profile, this arm did not proceed with the expansion phase. At data cutoff (10th November 2023), median follow-up was 13.8 (2.4-35.5, arm A) and 11.2 (0.2-36.9, arm B) months (mo). All pts discontinued treatment, mainly because of PD (74.1%). Discontinuations due to AEs were 4.5% and 4% in arms A and B, respectively. Incidence of treatment-related (1) any grade (G) TEAEs was 81.8% and 88% and (2) SAEs was 4.5% and 20% for arms A and B, respectively. G≥3 TEAEs occurring in ≥10% of pts are shown (Table). No treatment-related deaths were reported. Median PFS was 2.7 (95%CI, 1.5-4.1) and 3.8 (95%CI, 1.5-9.6) mo; median OS was 15.5 (95%CI, 11.8-19.2) and 11.5 (95%CI, 8.8-25.1) mo; and ORR was 9.1% and 36% for arms A and B, respectively. Conclusions: Combining IPA with CA and E presented an acceptable safety profile. However, adding IPA to CG was not tolerable. E + IPA showed promising efficacy regardless of PI3K/AKT status that merits further evaluation. Clinical trial information: NCT04464174 . [Table: see text]

Tazemetostat in combination with topotecan and pembrolizumab in patients with recurrent small cell lung cancer.

TPS8130 Background: Small-cell lung cancer (SCLC) is the most fatal type of lung cancer characterized by exquisite chemo-sensitivity at diagnosis and chemoresistance at relapse. Despite a highly mutated genome, patients with SCLC derive little benefit from immunotherapy. EZH2 (enhancer of zeste homolog 2) is a master epigenetic regulator of SCLC neuroendocrine cell fate and plasticity. EZH2 inhibition 1) promotes upregulation of Schlafen 11 (SLFN11) which irreversibly blocks replication in response to DNA damaging agents and 2) enhances intrinsic immune signaling, leading to constitutive MHC I recovery, sensitizing resistant SCLC models to DNA damaging chemotherapy and immunotherapy. Tazemetostat is a selective oral EZH2 inhibitor. Methods: This is an investigator-initiated, NCI Cancer Therapy Evaluation Program (CTEP) sponsored, phase I dose escalation and dose expansion study which will evaluate safety and tolerability of combination of tazemetostat with topotecan, a selective TOP1 inhibitor, and programmed cell death protein 1 (PD-1) inhibitor antibody pembrolizumab. Adult patients with relapsed/recurrent SCLC after at least platinum doublet (limited stage-SCLC) or chemo-immunotherapy (extensive stage-SCLC) and ECOG performance 0-1 are eligible. The regimen design involves a 7-day “run-in” of oral tazemetostat BID followed by 21-day cycles of tazemetostat (1-21 days), intravenous (IV) topotecan (day 1-5) and IV pembrolizumab (Day 1). The dose escalation cohort aims to determine safety and optimal doses of tazemetostat and topotecan (with standard dose of pembrolizumab) using a 3+3 design by assessing for dose limiting toxicities. The dose expansion cohort aims to assess safety, tolerability and preliminary efficacy of the combination in 15 additional patients with relapsed SCLC. The study involves collection of mandatory biopsies at pre-treatment and post-treatment (cycle 1) to gain insights into mechanism of action and resistance of the combination using single cell and spatial transcriptomic approaches. For more questions regarding enrollment and eligibility please contact Rasa.vilimas@nih.gov or anish.thomas@nih.gov . Clinical trial information: NCT05353439 .

Phase 2 study of xevinapant + chemoradiotherapy (CRT) vs placebo + CRT in patients with unresected locally advanced squamous cell carcinoma of the head and neck (LA SCCHN): A post hoc activity analysis by blinded independent review committee evaluation.

e18039 Background: The randomized, placebo-controlled, double-blind, phase 2 study (NCT02022098) of xevinapant + CRT demonstrated for the first time improved efficacy outcomes, including 5-year overall survival, when adding a new treatment modality to CRT for patients (pts) with unresected LA SCCHN. Here, we report a post hoc analysis comparing selected efficacy endpoints by blinded independent review committee (BIRC) evaluation with previously reported outcomes by investigator analysis. Methods: The study design was previously published (Sun X-S, et al. Lancet Oncol. 2020;21[9]:1173-87). Pts received oral xevinapant 200 mg/day (Days 1–14 of a 21-day cycle for 3 cycles), or matched placebo, with standard-of-care cisplatin-based CRT. Progression-free survival (PFS), duration of response (DOR), best overall response (BOR), and time to response (TTR) were independently evaluated by a two-reader, sequential time point presentation, batch read mode paradigm. Radiologists were blinded to investigator assessments. Discrepancies were adjudicated by a blinded, independent third radiologist. Results: All 96 pts randomized into the study (n=48 in each arm) were evaluated by BIRC. Response concordance between BIRC and investigator assessment was 84.4%. There were 31 PFS events by BIRC (xevinapant + CRT, 11 events; placebo + CRT, 20 events) and 38 PFS events by investigator (xevinapant + CRT, 12 events; placebo + CRT, 26 events) assessment, respectively. Xevinapant + CRT reduced the risk of disease progression (by BIRC) or death vs placebo + CRT by 62% (HR, 0.38 [95% CI, 0.18–0.79]; p=0.0099); median PFS was not reached (NR) vs 20.8 months, respectively. PFS outcomes by investigator analysis (HR, 0.33; 95% CI, 0.17–0.67; p=0.0019) were similar. DOR (by BIRC) was prolonged with xevinapant + CRT vs placebo + CRT (median, NR vs 31.4 months; HR, 0.31 [95% CI, 0.11–0.83]; p=0.0196), which was similar to outcomes by investigator analysis (adjusted HR, 0.21; 95% CI, 0.08–0.54; p=0.0011). Complete response (CR; by BIRC) was the most frequent BOR in both arms (xevinapant + CRT, 28 [58.3%]; placebo + CRT, 19 [39.6%]); the CR rate was greater in pts treated with xevinapant + CRT vs pts treated with placebo + CRT (odds ratio, 2.56; 95% CI, 1.07–6.13; p=0.0344). The CR rate trends by BIRC evaluation were similar to those by investigator analysis (xevinapant + CRT, 31 [64.4%]; placebo + CRT, 26 [54.2%]). A difference in TTR (by BIRC) favoring xevinapant + CRT over placebo + CRT was also observed (HR, 0.65 [95% CI, 0.39–1.07]). Conclusions: While fewer PFS events were observed by BIRC than by investigator assessment, the BIRC results were generally consistent with those of the investigators, with only minor differences in endpoint outcomes. Clinical trial information: NCT02022098 .

An open-label, single-center phase II trial of cadonilimab (an anti-PD-1/CTLA-4 bispecific antibody) in combination with platinum-based dual-drug neoadjuvant chemotherapy for locally advanced, resectable head and neck squamous cell carcinoma.

6044 Background: Consensus on neoadjuvant treatment strategies for resectable head and neck squamous cell carcinoma (HNSCC) is not proposed currently. Preclinical and clinical findings suggested that PD-1/CTLA-4 bispecific antibodies may have synergistic anti-tumor activity. This study aimed to explore the safety and activity of cadonilimab in combination with platinum-based dual-drug neoadjuvant chemotherapy in locally advanced, resectable HNSCC. Methods: In this open-label phase II trial, eligible patients with untreated locally advanced, resectable HNSCC (T2N2-3M0、T3-4N0-3M0; stage III-IV, AJCC 8th Edition) were enrolled to receive cadonilimab (10 mg/kg) and platinum-based dual-drug [docetaxel (75 mg/m2) plus cisplatin (60 mg/m2)] on day 1 of each 21-day cycle for three cycles, followed by surgery and postoperative adjuvant therapy. The primary endpoint was objective response rate (ORR) per RECIST1.1. Secondary endpoints included pathologic complete response (pCR), safety, disease-free survival (DFS), and overall survival (OS). Results: Between July 2023 and December 2023, 24 patients were enrolled (median age, 55 years [range 34–69]; 21 men [87.5%]), tumors were located in the oral cavity (10/24, 41.7%), hypopharynx (8/24, 33.3%) and larynx (6/24, 25.0%), 20 (83.3%) patients were clinical T3/4 while 10 patients (41.7%) ≥N2 . After completion of neoadjuvant therapy, the ORR was 87.5% (21/24). Of the 24 patients, 12 (50.0%) patients reached pCR. Treatment-related adverse events (TRAEs) occurred in 14 (58.3%) patients. Grade 3-4 TRAEs were reported in 4 (16.7%) patients, including rash (12.5%), pruritus (12.5%) and Guillain-Barre syndrome (4.2%). DFS and OS data were not yet mature as of the cutoff date (January 1,2024). Conclusions: Cadonilimab plus platinum-based dual-drug neoadjuvant chemotherapy achieved favorable ORR and pCR with manageable toxicities in patients with HNSCC. Follow-up is still underway to obtain long-term survival data. Clinical trial information: NCT06023875 .

Overall survival outcomes of phase II GECCOR-GB trial, a multicentre trial of adjuvant adjuvant gemcitabine plus cisplatin (GC) and capecitabine with concurrent capecitabine radiotherapy (Cape-RT) for operated gallbladder cancer (GBC).

4124 Background: The optimal adjuvant treatment for gallbladder cancer (GBC) after surgery remains unclear. We previously reported 1 year of disease-free survival (DFS) of adjuvant gemcitabine plus cisplatin (GC) or capecitabine with concurrent capecitabine radiotherapy (Cape-RT). Here, we present the secondary endpoint of the 3-year outcomes of the GECCOR-GB study. Methods: We conducted a multicenter, open-label, non-comparative randomized phase II trial of adjuvant GC or Cape-RT in patients with resected GBC. Patients were randomized 1:1 to receive either GC (gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 on days 1 and 8 of a 21-day cycle for 6 cycles) or Cape-RT arm {Capecitabine 1000 mg/m2 BD on days 1–14, q 3 weeks for 2-4 cycles followed by chemoradiation (RT: 45 Gy over 25 fractions concurrent with capecitabine: 825 mg/m2 BD) followed by 2-4 cycles of capecitabine for a total of 6 cycles}. The primary endpoint was DFS, and the secondary endpoints were overall survival (OS), safety, and treatment completion rates. Results: We enrolled 90 patients at 3 centers in India between May 2019 and February 2022 and randomly assigned 45 patients to each arm. In the GC arm, the median age of patients was 56 (33–72) years, and 23 (51%) patients were in stage II. While in the cape-RT arm, the median age was 55 (26–69) years, with 27 (60%) patients in stage II. The 3-year DFS was 54.3% in the GC arm and 70.7% in the Cape-RT arm, respectively. The 3-year OS was 75% in the GC arm and 73% in the Cape-RT arm, respectively. The 3-year OS in stage II patients (n = 23) in the GC arm was 91.3%, while in the cape-RT arm (n = 27), it was 91.9%. Median OS in stage III patients (n = 22) was 39.1 (95% CI, 33.4–44.6) months in the GC arm, while in the cape-RT (n = 18), it was 23.2 (95% CI, 7.0–39.4) months. Conclusions: Adjuvant GC arm patients, especially those in stage III, had encouraging OS at 3 years, while both GC and adjuvant Cape-RT arms had excellent 3-year OS, reaching more than 90% in patients with stage II-operated GBC. Further studies are needed to compare and validate these findings for GBC patients. GECCOR-GBwas led by Tata Memorial Hospital (TMC), Mumbai. Clinical trial information: CTRI/2019/05/019323.

A phase II umbrella clinical trial of advanced salivary gland cancer based on molecular typing.

e18062 Background: Salivary gland cancers (SGCs) exhibit high heterogeneity in molecular and genomic characteristics, which provides a basis for targeted therapies of SGCs. Until recently, the gene targets of precision therapy drugs mainly included HER2, NTRK, TROP2, androgen-receptor (AR), etc. Herein, we report the preliminary result of a single-center, open-label, phase II umbrella clinical trial evaluating the efficacy and safety of molecular subtype-guided precision therapy for advanced salivary gland cancer (NCT05924256). Methods: Patients (pts) diagnosed as advanced SGC were recruited into 3 arms according to genetic subtypes. Pts with HER2 mutation/amplification or HER2 overexpression (IHC 3+ or IHC 2+/ISH+) will be assigned to arm 1 and receive SHR-A1811(anti-HER2) 4.8 mg/kg i.v. on day 1 of each 21-day cycle. IHC AR+ pts will be assigned to arm 2 and will receive rezvilutamide 240mg p.o. qd plus leuprolide 3.75mg s.c. on day 1 of each 28-day cycle. Pts with HER2 negative and AR negative will be assigned to arm 3 to receive SHR-A1921(anti-TROP2) 3.0 mg/kg or 4.0 mg/kg i.v. on day 1 of each 21-day cycle. A Simon’s two-stage optimal design was applied to each arm. The primary endpoint was the objective response rate (ORR) per RECIST1.1. Secondary endpoints included adverse events (AEs), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), etc. Results: Between Aug 2, 2023, and Jan 21, 2024, 21 pts were enrolled (arm 1/2/3: 9/5/7 pts, respectively). All pts were included in the safety set. In arm 1, of 6 evaluable pts, the unconfirmed ORR and DCR accounted for 100.0% and 100.0%, respectively. The most common treatment-related adverse events (TRAEs) in arm 1 were decreased lymphocyte count, neutrophil count, and decreased appetite (44.4% each). In arm 2, of 5 evaluable pts, the unconfirmed ORR and DCR were 20.0% and 100.0%, respectively. Rash, alanine aminotransferase increased, aspartate aminotransferase increased, and gamma-glutamyltransferase increased (20% each) were the most common TRAEs. In arm 3, of 6 evaluable pts, the unconfirmed ORR and DCR were 33.3% and 66.7%, respectively. In this arm, the most common TRAEs were stomatitis and vomiting (42.9% each). Conclusions: This molecular subtype-guided precision therapy for advanced salivary gland cancer showed promising results with acceptable toxicity. Clinical trial information: NCT05924256 .