Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): Expanded efficacy and safety analyses from CheckMate 648.

O-3 Nivolumab (NIVO) plus chemotherapy (chemo) or ipilimumab (IPI) vs chemo as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): Expanded efficacy and safety analyses from CheckMate 648

290 Background: NIVO + chemo and NIVO + IPI demonstrated superior overall survival (OS) vs chemo in CheckMate 648 (NCT03143153), leading to approvals in the US, EU, Japan, and other countries. We report longer follow-up results. Methods: Adults with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W) or chemo. Primary endpoints were OS and progression-free survival (PFS) per blinded independent central review (BICR). Hierarchical testing was done first in patients (pts) with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%, then in all randomized pts. Results: 970 pts were randomized to NIVO + chemo, NIVO + IPI, or chemo. With 29-mo minimum follow-up, NIVO + chemo and NIVO + IPI continued to show improvement in OS vs chemo, including higher 24-mo OS rates, in pts with tumor cell PD-L1 ≥ 1% and all randomized pts. Responses were more durable and a larger proportion of responders had a duration of response (DOR) ≥ 24 mo with NIVO + chemo and NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥ 1% (22%, 36%, 13%, respectively) and all randomized pts (21%, 29%, 13%). Additional efficacy data by PD-L1 status will be presented. Any-grade treatment-related adverse events (TRAEs) occurred in 96% (grade 3/4, 49%) of pts with NIVO + chemo, 80% (33%) with NIVO + IPI, and 90% (36%) with chemo. Any-grade TRAEs leading to discontinuation occurred in 35% of pts with NIVO + chemo, 19% with NIVO + IPI, and 21% with chemo. Treatment-related deaths occurred in 2% of pts in each arm. Conclusions: NIVO + chemo and NIVO + IPI continued to demonstrate clinically meaningful survival benefit vs chemo, durable objective responses, and acceptable safety profiles with longer follow-up. This further supports each regimen as a new 1L treatment option for advanced ESCC. Clinical trial information: NCT03143153 . [Table: see text]

4034 Background: NIVO + chemo and NIVO + IPI are approved for the treatment of advanced ESCC in the US, EU, Japan, and many other countries based on the results from CheckMate 648 (NCT03143153). Here, we report 45-mo follow-up results. Methods: Adults with previously untreated, unresectable advanced, recurrent, or metastatic ESCC were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W) or chemo. The primary endpoints were overall survival (OS) and progression-free survival (PFS) per blinded independent central review (BICR) in patients (pts) with tumor cell programmed death ligand 1 (PD-L1) ≥ 1%. Results: In total, 970 pts were randomized to NIVO + chemo, NIVO + IPI, or chemo. With 45-mo minimum follow-up, NIVO + chemo and NIVO + IPI demonstrated continued OS benefit and higher 45-mo OS rates vs chemo in pts with tumor cell PD-L1 ≥ 1% and all randomized pts (Table). Duration of response (DOR) was longer (Table) and the proportion of responders with DOR ≥ 45 mo was greater with NIVO + chemo and NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥ 1% (7% and 23% vs 0%, respectively) and all randomized pts (14% and 18% vs 6%). Any-grade treatment-related adverse events (TRAEs) occurred in 96% of pts with NIVO + chemo, 80% with NIVO + IPI, and 90% with chemo; grade 3/4 TRAEs occurred in 49%, 33%, and 37% of pts, respectively. No additional TRAEs leading to discontinuation and no new treatment-related deaths were reported with longer follow-up. Conclusions: After 45 mo of follow-up, NIVO + chemo and NIVO + IPI continued to demonstrate clinically meaningful survival benefit and more durable responses vs chemo, with no new safety signals. These results further support NIVO + chemo and NIVO + IPI as 1L treatment options for advanced ESCC. Clinical trial information: NCT03143153 . [Table: see text]

LBA4001 Background: NIVO demonstrated superior overall survival (OS) vs chemo in previously treated patients (pts) with ESCC (ATTRACTION-3). We report OS and progression-free survival (PFS) from CheckMate 648, the first global phase III study to evaluate both an immuno-oncology (I-O)/chemo combination and an I-O/I-O combination in advanced ESCC. Methods: Adults with previously untreated, unresectable advanced, recurrent or metastatic ESCC were enrolled regardless of tumor cell PD-L1 expression. Pts were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), or chemo alone. Primary endpoints for both comparisons were OS and PFS per blinded independent central review (BICR) in pts with tumor cell PD-L1 ≥ 1%. Hierarchically tested secondary endpoints included OS and PFS in all randomized pts. Results: 970 pts were randomized to NIVO + chemo, NIVO + IPI, and chemo arms (49% with tumor cell PD-L1 ≥ 1%). With 13 months (mo) minimum follow-up, NIVO + chemo and NIVO + IPI led to statistically significant improvement in OS vs chemo in pts with tumor cell PD-L1 ≥ 1% and all randomized pts (Table). Statistically significant PFS benefit was also observed for NIVO + chemo vs chemo (HR 0.65 [98.5% CI 0.46–0.92]; P = 0.0023) in pts with tumor cell PD-L1 ≥ 1%. PFS in NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥ 1% did not meet the prespecified boundary for significance. The objective response rate (per BICR) was 53% (NIVO + chemo), 35% (NIVO + IPI), and 20% (chemo) in pts with tumor cell PD-L1 ≥ 1% and in all randomized pts was 47%, 28%, and 27%, respectively; longer median (95% CI) duration of response was observed vs chemo for pts with tumor cell PD-L1 ≥ 1%: 8.4 (6.9–12.4), 11.8 (7.1–27.4), and 5.7 (4.4–8.7) mo and for all randomized pts: 8.2 (6.9–9.7), 11.1 (8.3–14.0), and 7.1 (5.7–8.2) mo, respectively. No new safety signals were identified (Table). Conclusions: NIVO plus chemo and NIVO plus IPI both demonstrated superior OS vs chemo, along with durable objective responses and acceptable safety, in pts with advanced ESCC, and each represents a potential new 1L treatment option. Clinical trial information: NCT03143153. [Table: see text]

BackgroundFirst‐line nivolumab plus chemotherapy and nivolumab plus ipilimumab both demonstrated significant overall survival (OS) benefit versus chemotherapy in previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC) in the CheckMate 648 trial, leading to approvals of both nivolumab‐containing regimens in many countries. We report longer‐term follow‐up data.MethodsThis open‐label, phase III trial (NCT03143153) enrolled adults with previously untreated, unresectable, advanced, recurrent, or metastatic ESCC. Patients were randomized 1:1:1 to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy. Primary endpoints were OS and progression‐free survival (PFS) by blinded independent central review. Hierarchical testing was performed first in patients with tumor cell programmed death ligand 1 (PD‐L1) expression of ≥1% and then in the overall population.ResultsA total of 970 patients were randomly assigned. After 29 months of minimum follow‐up, nivolumab plus chemotherapy continued to demonstrate improvement in OS versus chemotherapy (hazard ratio [HR] = 0.59 [95% CI: 0.46–0.76]) in patients with tumor cell PD‐L1 expression of ≥1% and in the overall population (HR = 0.78 [95% CI: 0.65–0.93]) and with nivolumab plus ipilimumab versus chemotherapy (HR = 0.62 [95% CI: 0.48–0.80]) in patients with tumor cell PD‐L1 expression of ≥1% and in the overall population (HR = 0.77 [95% CI: 0.65–0.92]). In patients with tumor cell PD‐L1 expression of ≥1%, nivolumab plus chemotherapy demonstrated PFS benefit versus chemotherapy (HR = 0.67 [95% CI: 0.51–0.89]); PFS benefit was not observed with nivolumab plus ipilimumab versus chemotherapy (HR = 1.04 [95% CI: 0.79–1.36]). Among all treated patients (n = 936), Grade 3–4 treatment‐related adverse events were reported in 151 (49%, nivolumab plus chemotherapy), 105 (32%, nivolumab plus ipilimumab), and 110 (36%, chemotherapy) patients.ConclusionsNivolumab plus chemotherapy and nivolumab plus ipilimumab continued to demonstrate clinically meaningful OS benefit versus chemotherapy with no new safety signals identified with longer follow‐up, further supporting use as first‐line standard treatment options for patients with advanced ESCC.

LBA11 - Nivolumab versus chemotherapy in advanced esophageal squamous cell carcinoma (ESCC): The phase III ATTRACTION-3 study

TPS255 Background: ESCC is the predominant histological subtype of esophageal cancer, particularly in Asian countries. Platinum-based chemotherapy is the first-line standard therapy for patients with unresectable, locally advanced, recurrent or metastatic ESCC. The FP regimen is recommended as the preferred treatment by guidelines. However, the survival benefit conferred by this therapy leaves considerable space for improvement, with median OS being less than 1 year. Blockade of the immune checkpoint receptors has shown clinical benefits in multiple tumor types. Recent studies combining standard treatments with checkpoint inhibitors have shown encouraging efficacy and favorable safety profile in patients with unresectable, locally advanced, recurrent or metastatic ESCC. CS1001 (sugemalimab) is the first full-length, fully human immunoglobin G4 (IgG4, s228p) anti-programmed death-ligand 1 (PD-L1) monoclonal antibody developed by the OMT transgenic rat platform. In an ongoing Phase Ib trial, CS1001 in combination with FP regimen demonstrated an ORR of 67.6% (25/37) and an mPFS of 9.0 months with a manageable safety profile in unresectable, locally advanced or distantly metastatic ESCC (19 Feb 2020 data cutoff; Shen, L., et al, ESMO 2020). Methods: CS1001-304 is a randomized, double-blind Phase III study to compare the efficacy and safety of FP regimen with CS1001 or placebo as first-line treatment in ESCC. The study enrolls patients with histologically or cytologically confirmed unresectable locally advanced, recurrent or metastatic ESCC who have ECOG PS of 0-1, patients are not eligible for curative therapy (curative surgery or definitive chemoradiotherapy), and have not received any prior systemic anti-tumor therapy for locally advanced or metastatic disease. Approximately 540 patients will be randomized at 2:1 into CS1001 + FP and placebo + FP arms respectively, stratified by PD-L1 expression status (PD-L1 expression < 1% vs ≥ 1% and < 10% vs ≥10%), ECOG PS (0 vs 1) and distant metastasis (no vs yes). Patients randomized to either arm will receive FP regimen (fluorouracil: 800 mg/m2/day, continuous intravenous infusion [IV], D1-4 of each cycle; cisplatin: 80 mg/m2, IV, D1 of each cycle), Q3W for up to 6 cycles in combination with CS1001 1200 mg or placebo (IV, D1 of each cycle), Q3W for up to 24 months. AEs will be monitored throughout the study and graded per NCI CTCAE v5.0. Tumor response will be assessed by RECIST v1.1 every 6 weeks in the first 12 months, and every 12 weeks thereafter. The primary endpoints are blinded independent central review (BICR)-assessed PFS and OS. Secondary endpoints include investigator-assessed PFS, BICR and investigator-assessed ORR and DoR, safety, PK profile, and immunogenicity. The study is actively enrolling patients in over 60 sites in China. Clinical trial information: NCT04187352.

363 Background: Platinum-based chemotherapy is the standard first-line treatment for advanced or metastatic ESCC. Recently, the combination of PD-(L)1 pathway blockade with chemotherapy has shown synergistic efficacy in a few clinical trials. SHR-1701 is a novel bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II. The purpose of this ongoing phase II trial (ChiCTR2000039909) was to evaluate the efficacy and safety of SHR-1701 combined with chemotherapy for unresectable locally advanced, recurrent or metastatic ESCC in China. Methods: This trial enrolled systemic treatment-naive patients(pts) with histologically or cytologically confirmed unresectable locally advanced, recurrent or metastatic ESCC who had ECOG PS of 0-1. Eligible pts received SHR-1701 (30mg/kg, iv, d1, q3w) combined with up to 6 cycles of albumin-bound paclitaxel (125mg/m2, iv, d1, d8, q3w) and cisplatin (75mg/m2, iv, d1, q3w). For those without progressive disease, maintenance treatment was administrated with SHR-1701 monotherapy until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression free survival (PFS), overall survival (OS), disease control rate (DCR), safety and biomarkers. Results: As of September 21, 2022, 18 pts were enrolled. The median age was 67.5 years (range: 46–75 years) and 16 (88.9%) were male. 10 of the pts (55.6%) presented with distant metastasis. 14 pts were included in the efficacy analysis and 17 were in the safety analysis. The ORR and DCR were 85.7% and 100.0%, respectively. One patient achieved a complete response (CR) which will reach confirmation at next visit. 11 pts had partial response (PR), including 9 confirmed PR, one pending confirmation PR, and one unconfirmed PR. In addition, one PR patient got a CR target lesion. Grade 3-4 treatment-related adverse events (AEs) were observed in 23.5% of pts, including neutropenia (11.8%), leukopenia (5.9%), anemia (5.9%), emesis (5.9%) and rash (5.9%). Immune-related AEs (irAEs) were observed in 52.9%, and only one grade 3 irAE of rash occurred. Conclusions: SHR-1701 plus chemotherapy showed potential clinical benefits with acceptable toxicity as first-line treatment, and it might be a favorable option for pts with advanced ESCC. Clinical trial information: ChiCTR2000039909 .

TPS4209 Background: There is a substantial need for more effective and tolerable first-line treatment options for patients with advanced ESCC. B7-H3 is a type 1 transmembrane protein that is highly expressed in several cancers, including ESCC, and is associated with a poor prognosis. Ifinatamab deruxtecan (I-DXd; formerly DS-7300a/MK-2400) is a B7-H3–directed antibody-drug conjugate comprising a humanized anti–B7-H3 IgG1 monoclonal antibody (ifinatamab) covalently linked to a potent topoisomerase I inhibitor payload (DXd; an exatecan derivative) by a cleavable linker. In the phase 1/2 DS7300-A-J101 study, I-DXd monotherapy showed promising antitumor activity in participants (pts) with advanced ESCC. KEYMAKER-U06 is an open-label, phase 1/2, umbrella platform study designed to evaluate investigational agents with or without pembrolizumab and/or chemotherapy for advanced gastroesophageal cancer. Substudy 06E (NCT06780111) will be conducted to evaluate I-DXd plus pembrolizumab with or without chemotherapy as first-line therapy for advanced ESCC. Methods: Eligible pts are aged ≥18 years with previously untreated, histologically or cytologically confirmed, locally advanced unresectable or metastatic ESCC, measurable disease per RECIST v1.1 by investigator review and verified by blinded independent central review (BICR), and an Eastern Cooperative Oncology Group performance status of 0 or 1. Pts will be assigned to 1 of 4 treatment arms: arm 1 (reference treatment; pembrolizumab 200 mg IV Q3W for ≤35 cycles plus chemotherapy [mFOLFOX6: oxaliplatin 85 mg/m 2 IV Q2W plus 5-FU 400 mg/m 2 (bolus) and 2400 mg/m 2 (continuous) IV Q2W plus leucovorin 400 mg/m² IV Q2W]); arm 2 (I-DXd 12 mg/kg IV Q3W plus pembrolizumab); arm 3 (I-DXd 12 mg/kg plus pembrolizumab plus 5-FU 400 mg/m 2 [bolus] and 2400 mg/m 2 [continuous] IV Q2W plus leucovorin 400 mg/m² IV Q2W); and arm 4 (I-DXd [8 mg/kg or 12 mg/kg] IV plus pembrolizumab plus 5-FU 2400 mg/m 2 IV and oxaliplatin 60 mg/m 2 ). Approximately 209 pts will be enrolled. A safety lead-in phase with ≤29 pts will be conducted in arms 2 (n ≤6), 3 (n ≤10), and 4 (n ≤13) using a Bayesian optimal interval design to confirm the safety and recommended phase 2 dose (RP2D; arm 4 only) of I-DXd in combination with other agents; this phase will be conducted sequentially, starting with arm 2, followed by arms 3 and 4. Thereafter, ≤180 pts will be included in the randomized phase (≤60 in arm 1; ≤40 each in arms 2-4). Pts will be randomly assigned 1:2 to arm 1 and the investigational arms. Primary outcomes are safety and tolerability, RP2D of I-DXd, and objective response rate per RECIST v1.1 by BICR for the selected dose. Secondary outcomes include DOR and PFS per RECIST v1.1 by BICR, OS, and pharmacokinetics of I-DXd in combination with other agents. Enrollment is ongoing. Clinical trial information: NCT06780111 .

398 Background: At 4-y follow-up, 1L NIVO + chemo continued to demonstrate clinically meaningful overall survival (OS) and progression-free survival (PFS) benefit vs chemo with acceptable safety in patients (pts) with advanced non-HER2+ GC/GEJC/EAC from CheckMate 649. We report efficacy and safety results of NIVO + chemo vs chemo at 5-y follow-up. Methods: Adults with previously untreated, unresectable, advanced or metastatic, non-HER2+ GC/GEJC/EAC were enrolled, regardless of programmed death ligand 1 (PD-L1) expression. Pts were randomized to NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Primary endpoints for NIVO + chemo vs chemo were OS and PFS by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: Pts were randomized to NIVO + chemo (n = 789) or chemo (n = 792). NIVO + chemo continued to show OS and PFS benefit vs chemo in pts with PD-L1 CPS ≥ 5, pts with PD-L1 CPS ≥ 1, and all randomized pts at 60-month (mo) minimum follow-up (Table). OS rates at 60-mo were higher with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5, pts with PD-L1 CPS ≥ 1, and all randomized pts (Table), and OS benefit with NIVO + chemo continued to be observed in most prespecified subgroups. Objective response rates (ORRs) were higher and responses were more durable with NIVO + chemo vs chemo in pts with PD-L1 CPS ≥ 5, pts with PD-L1 CPS ≥ 1, and all randomized pts (Table). No new safety signals were identified. Conclusions: These results represent the first report of 5-y follow-up for anti–PD-1 + chemo combination therapy in GC/GEJC/EAC to our knowledge. NIVO + chemo continued to provide sustained long-term survival vs chemo with an acceptable safety profile after 5 y of follow-up. These data continue to support the use of NIVO + chemo as a standard 1L treatment for advanced GC/GEJC/EAC. Clinical trial information: NCT02872116 . Efficacy PD-L1 CPS ≥ 5 PD-L1 CPS ≥ 1 All randomized NIVO + chemo(n = 473) Chemo (n = 482) NIVO + chemo (n = 641) Chemo (n = 656) NIVO + chemo (n = 789) Chemo (n = 792) mOS (95% CI), mo 14.4 (13.1–16.2) 11.1 (10.1–12.1) 13.8 (12.4–14.8) 11.4 (10.7–12.3) 13.7 (12.4–14.5) 11.6 (10.9–12.5) HR (95% CI) 0.71 (0.61–0.81) 0.76 (0.67–0.85) 0.79 (0.71–0.88) 60-mo OS rate (95% CI), % 16 (12–19) 6 (4–9) 13 (11–16) 5 (4–7) 12 (10–14) 6 (4–8) mPFS a (95% CI), mo 8.3 (7.0–9.4) 6.1 (5.6–6.9) 7.5 (7.0–8.5) 6.9 (6.2–7.1) 7.8 (7.1–8.6) 6.9 (6.7–7.2) HR (95% CI) 0.71 (0.61–0.82) 0.77 (0.68–0.87) 0.79 (0.71–0.89) ORR a,b (95% CI), % 60 (55–65) 45 (40–50) 60 (55–64) 46 (42–51) 58 (54–62) 46 (42–50) mDOR a,c (95% CI), mo 9.6 (8.3–12.4) 7.0 (5.7–8.0) 8.6 (7.9–10.5) 6.9 (5.8–7.6) 8.5 (7.7–9.9) 6.9 (5.9–7.6) a Per BICR. b In pts with measurable target lesions at baseline. c In all measurable responders. DOR, duration of response; m, median.

BackgroundThe published evidence from several randomized controlled clinical trials of immunotherapy for advanced esophageal squamous cell carcinoma has shown promising results. This study aimed to investigate the efficacy and safety of immune checkpoint inhibitor treatment in esophageal squamous cell carcinoma.MethodsPubMed, Web of Science, Cochrane Library, and Embase databases were searched for relevant articles published before December 30, 2020. The data for efficacy and safety of immune checkpoint inhibitor treatment were subjected to meta-analysis.ResultsSeven clinical trials comprising 1733 patients were included. The results showed that immune checkpoint inhibitor treatment as second- or later-line treatment was associated with an increased risk of the objective response rate (relative risk: 1.82, 95% confidence interval: 0.82–4.04; P=0.002) and median overall survival (hazard ratio: 0.75, 95% confidence interval: 0.67–0.85; P<0.001) compared with chemotherapy in locally advanced or metastatic esophageal squamous cell carcinoma. Moreover, immune checkpoint inhibitor treatment was associated with significant improvement in median overall survival (hazard ratio: 0.61, 95% confidence interval: 0.48–0.77, P<0.001) compared with chemotherapy in the programmed death-ligand 1 (PD-L1)-positive population. However, immune checkpoint inhibitor treatment was also effective in all patients independent of PD-L1 expression. The most common grade ≥3 treatment-related adverse events with immune checkpoint inhibitor therapy were anemia, asthenia, rash, fatigue, decreased appetite, diarrhea, pneumonia, decreased neutrophil count, and vomiting. Patients undergoing immune checkpoint inhibitor therapy was associated with a decreased risk of treatment-related adverse events (relative risk: 0.82, 95% confidence interval: 0.62–1.08; P<0.001) and grade ≥3 treatment-related adverse events (relative risk: 0.50, 95% confidence interval: 0.42–0.60; P<0.001) compared with those undergoing chemotherapy.ConclusionsImmune checkpoint inhibitors as second- or later-line therapy may improve overall response rate and overall survival but not all oncological outcomes for patients with locally advanced or metastatic esophageal squamous cell carcinoma. Patients treated with immune checkpoint inhibitors might experience fewer treatment-related adverse events of any grade, but specifically grade ≥3, compared with those treated with chemotherapy.

Safety and efficacy of tislelizumab plus chemotherapy for first-line treatment of advanced esophageal squamous cell carcinoma and gastric/gastroesophageal junction adenocarcinoma.

364 Background: The optimal therapies for patients with advanced esophageal squamous cell carcinoma (ESCC) who have progressed after immune checkpoint inhibitors (ICIs) are unclear. This phase II single-arm study aimed to assess the efficacy and safety of re-challenge with camrelizumab plus apatinib in this population. Methods: This study enrolled patients with unresectable locally advanced, locally recurrent, or metastatic ESCC who had experienced prior progression on ICI treatment. Enrolled patients received camrelizumab 200 mg intravenously every two weeks along with daily oral apatinib 250 mg. Treatment continued until disease progression, unacceptable toxicity, or patient withdrawal of consent. The primary endpoint was the confirmed objective response rate (ORR). Secondary endpoints included disease control rate (DCR), duration of response (DOR), time to response (TOR), progression-free survival (PFS), overall survival (OS), 3- and 6-month PFS rates, 6-, 9- and 12-month OS rates, and safety. Results: From September 1, 2021, to March 29, 2023, 49 eligible patients were enrolled and given treatment. Among 38 treated patients who had at least one post-baseline efficacy measurement, the ORR and confirmed ORR were 36.8% (95% CI 21.8–54.0) and 13.2% (95% CI 4.4–28.1); the DCR was 89.5% (95% CI 75.2–97.1); the median DOR was 3.0 months; and the median TOR was 2.2 months. Among the 49 treated patients, the median PFS was 4.6 months (95% CI 3.8–6.5) and OS was 7.5 months (95% CI 5.5–13.6). Patients who were both PD-L1 positive and had responded to previous ICI therapy had the longest median PFS (5.7 months, 95% CI 3.9–not reached) and OS (9.6 months, 95% CI 7.5–not reached). Grade ≥ 3 treatment-related adverse events occurred in 34.7% of patients (17/49). Conclusions: This study showed promising efficacy and an acceptable safety profile of camrelizumab plus apatinib for patients with advanced ESCC who had progressed after ICI therapy. The subset of patients who were both PD-L1 positive and had a prior ICI response seemed to benefit most. Clinical trial information: NCT03736863 .

BackgroundCadonilimab, a bispecific antibody simultaneously targeting programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4, may further boost antitumor activity compared with PD-1 or programmed cell death ligand 1 (PD-L1) inhibitors. Here, we evaluated the safety and efficacy of cadonilimab combined with chemotherapy as the first-line treatment in advanced esophageal squamous cell carcinoma (ESCC).MethodsTreatment-naïve patients with unresectable locally advanced or metastatic ESCC were eligible. Cadonilimab combined with paclitaxel or nab-paclitaxel and cisplatin was administrated for up to six cycles, then cadonilimab monotherapy continued as maintenance until progressive disease or unacceptable toxicity, with a maximum of 24 months. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Plasma cell-free DNA samples were collected before and after treatment and prepared for DNA methylation level sequencing.ResultsAs of September 27, 2024, 43 patients were enrolled with a median age of 61 years (range 44–75), 39.5% had PD-L1 combined positive score ≥10 and 95.3% had distant metastases. The ORR was 81.4% (95% CI 66.6% to 91.6%) and DCR was 97.7% (95% CI 86.2% to 99.9%). The median PFS was 7.10 months (95% CI 5.68 to 8.48) while OS remained immature. The mean pretreatment cytosine-phosphate-guanine (CpG) site methylation levels of APBA2, EPAS1, TRIM58, ITPKA and LINC00554 were significantly higher in responders than those in non-responders. Grade 3–4 treatment-related adverse events were reported in 53.5% (23/43) patients.ConclusionsCadonilimab combined with taxane and cisplatin as first-line treatment revealed encouraging antitumor activity and manageable safety in patients with advanced ESCC. DNA methylation level might be a potential biomarker for guiding patient outcomes.Trial registration numberNCT05522894.

Although antiprogrammed death 1 antibody plus chemotherapy has recently been approved for first-line esophageal squamous cell carcinoma (ESCC), antiprogrammed death-ligand 1 antibody may offer another combination option in this setting. In this multicenter, randomized, double-blinded phase 3 trial a total of 540 adults (aged 18-75 years) with unresectable, locally advanced, recurrent or metastatic ESCC and who had not received systemic treatment were enrolled. All patients were randomized at 2:1 to receive either sugemalimab (an anti-PD-L1 antibody; 1,200 mg) or placebo every 3 weeks for up to 24 months, plus chemotherapy (cisplatin 80 mg m-2 on day 1 plus 5-fluorouracil 800 mg m-2 day-1 on days 1-4) every 3 weeks for up to six cycles. At the prespecified interim analysis this study had met dual primary endpoints. With a median follow-up of 15.2 months, the prolongation of progression-free survival was statistically significant with sugemalimab plus chemotherapy compared with placebo plus chemotherapy (median 6.2 versus 5.4 months, hazard ratio 0.67 (95% confidence interval 0.54-0.82), P = 0.0002) as assessed by blinded independent central review. Overall survival was also superior with sugemalimab chemotherapy (median 15.3 versus 11.5 months, hazard ratio 0.70 (95% confidence interval 0.55-0.90, P = 0.0076). A significantly higher objective response rate (60.1 versus 45.2%) as assessed by blinded independent central review was observed with sugemalimab chemotherapy. The incidence of grade 3 or above treatment-related adverse events (51.3 versus 48.4%) was comparable between the two groups. Sugemalimab plus chemotherapy significantly prolonged progression-free survival and overall survival in treatment-naïve patients with advanced ESCC, with no unexpected safety signal. The ClinicalTrials.gov identifier is NCT04187352 .