First-in-Class Drugs Make Their Debut at ESMO 2026: Promising Readouts and Clinical Setbacks

At the 2026 European Society for Medical Oncology (ESMO) Congress, several global first-in-class (FIC) therapies delivered their inaugural clinical readouts, with some showing promise for further investigation while others encountered setbacks in clinical validation. This analysis examines the first clinical data presentations from select global FIC products at ESMO, including CSPC Pharmaceutical Group's PD-1/IL-15 bispecific fusion protein, Merck & Co.'s tri-functional NK cell engager MK-4464, and Ascentage Pharma's EZH2 PROTAC.

CSPC Pharmaceutical Group: JMT108 PD-1/IL-15 Bispecific Fusion Protein

JMT108 (SYS6090), developed by CSPC Pharmaceutical Group, represents a first-in-class PD-1/IL-15 bispecific fusion protein. At ESMO, the company presented first-in-human Phase I/II study results, focusing on preliminary efficacy and safety in patients with hepatocellular carcinoma (HCC) and colorectal cancer (CRC).

As of April 13, 2026, the study enrolled 13 HCC patients (8 receiving 0.3 mg/kg, 5 receiving 1 mg/kg) and 38 CRC patients (16 receiving 0.3 mg/kg, 21 receiving 1 mg/kg, 1 receiving 2 mg/kg). Among these, 76.9% (10/13) of HCC patients and 89.5% (34/38) of CRC patients had received at least two prior lines of therapy. Additionally, 92.3% (12/13) of HCC patients had prior immunotherapy exposure, while 73.7% (28/38) of CRC patients had liver metastases.

A total of 10 HCC patients (5 at 0.3 mg/kg, 5 at 1 mg/kg) and 19 CRC patients (9 at 0.3 mg/kg, 9 at 1 mg/kg, 1 at 2 mg/kg) received at least one post-baseline tumor assessment and were included in the efficacy analysis set (EAS).

In the EAS, the objective response rates (ORR) were 40.0% for HCC and 21.1% for CRC. Among previously immunotherapy-treated HCC patients (n=9), the ORR was 33%. For CRC patients with liver metastases (n=17), the ORR reached 23.5%.

Regarding safety, the incidence of Grade 3 or higher treatment-related adverse events (TRAEs) was 30.8% in HCC and 13.2% in CRC. Serious TRAE rates were 7.7% and 10.5%, respectively. TRAE-related discontinuation occurred in 0% of HCC patients and 2.6% of CRC patients. No treatment-related deaths were reported.

Based on these positive solid tumor results, CSPC Pharmaceutical Group is actively pursuing combination therapy exploration and plans to initiate pivotal clinical studies as soon as possible.

Merck & Co.: MK-4464 CEACAM5/CD16A/NKG2D Tri-functional NK Cell Engager

MK-4464 is a tri-functional NK cell engager targeting CEACAM5, CD16A, and NKG2D. The Phase I study presented at the congress evaluated its efficacy and safety, with or without pembrolizumab, in patients with specific advanced solid tumors.

The study enrolled 64 patients with known CEACAM5-high advanced tumors (including NSCLC, esophageal, gastric, pancreatic, and CRC), all of whom had previously received or been unable to tolerate all known treatments with clinical benefit. The monotherapy group included 38 patients, the pembrolizumab combination group had 22 patients, and 4 additional patients entered an exploratory arm including radiolabeled drug administration.

For efficacy, no objective responses were observed in the monotherapy group, yielding an ORR of 0%, though 4 patients achieved stable disease. In the pembrolizumab combination group, the ORR was 9%, including 1 complete response and 1 partial response.

Safety analysis showed TRAE rates of 74% and 82% in monotherapy and combination groups, respectively, with Grade 3 TRAE rates of 11% and 18%. Each group reported 1 dose-limiting toxicity (DLT): Grade 3 liver enzyme elevation in the monotherapy group and Grade 3 maculopapular rash in the combination group.

Shimei Pharma: CMDE005 EGFR/CD3 Bispecific Antibody

CMDE005 is a recombinant human anti-EGFR/CD3 enzyme-controlled bispecific antibody developed by Shimei Pharma based on its proprietary dual-antibody platform proBiTE, employing a "masking peptide" to block CD3 binding activity. The company reported safety and preliminary efficacy data for CMDE005 in refractory EGFR-positive solid tumors.

As of April 18, 2026, 30 patients received CMDE005 treatment (<6 mg: n=20; ≥6 mg: n=10). These heavily pretreated patients had a median of at least 3 prior therapy lines.

Preliminary efficacy in patients receiving ≥3 mg doses showed a disease control rate (DCR) of 60% (n=5) for non-small cell lung cancer (NSCLC) and 66.7% (n=3) for microsatellite stable colorectal cancer (MSS-CRC). One highly refractory MSS/KRAS G12D mutant CRC patient achieved stable disease.

CMDE005 demonstrated a favorable safety profile with no DLTs and no TRAEs leading to discontinuation. Immune effector toxicity was limited to Grade 1-2 cytokine release syndrome (CRS); no Grade 3 or higher CRS or immune-related neurotoxicity (ICANS) occurred. In the ≥6 mg dose group, EGFR-related adverse events were primarily gastrointestinal and dermatologic toxicities.

Roche: SAIL66 CLDN6/CD3/4-1BB Trispecific Antibody

SAIL66 is a trispecific antibody targeting CLDN6, CD3, and 4-1BB, developed by Chugai Pharmaceutical, a Roche subsidiary. The company presented first-in-human Phase I study results for SAIL66 in patients with CLDN6-positive locally advanced or metastatic solid tumors.

As of September 2, 2025, the study enrolled 22 CLDN6-positive patients, exploring both every-3-week (Q3W) and weekly step-up dosing (QW) regimens. Median treatment duration was 1.3 months (range: 0.03-13.14 months). Dosing regimens tested included 0.086, 0.5, 2.6, 9, 18, and 30 μg/kg Q3W, as well as 9/15 μg/kg starting/target doses QW.

The maximum tolerated dose (MTD) was 18 μg/kg Q3W; the weekly dosing regimen showed poorer tolerability. Results showed 0 patients achieving complete or partial response, with 9 patients achieving stable disease. Notably, 21 of 22 patients (95.5%) developed anti-drug antibodies (ADA), which correlated with reduced drug exposure.

For safety, 6 of 22 patients (27.3%) experienced Grade 3 or higher TRAEs. Among 20 evaluable patients for DLT, 3 experienced at least 1 DLT, including Grade 3 alanine aminotransferase elevation (n=2), aspartate aminotransferase elevation (n=3), or gamma-glutamyltransferase elevation (n=1).

Based on available data and the development portfolio at the time, Roche removed SAIL66 from its pipeline in 2025.

Ascentage Pharma: AXT-1003 EZH2 PROTAC

AXT-1003 is a first-in-class small molecule with dual EZH2 enzymatic inhibition and degradation functions, licensed from Novartis by Ascentage Pharma. Unlike other EZH2 inhibitors, AXT-1003 is a non-SAM competitive allosteric inhibitor of EZH2 enzymatic activity that directly degrades EZH2 through the ubiquitination pathway, potentially achieving superior therapeutic outcomes.

As of April 24, 2026, the first-in-human Phase I study enrolled 38 patients, with 63.1% having received at least 3 prior therapy lines. The 25 mg dose cohort was completed with no observed DLTs.

Among 20 evaluable patients, preliminary efficacy showed 1 patient achieving partial response (PR, with complete response of target lesions), and a DCR of 50.0%. Durable anti-tumor activity was observed in ovarian clear cell carcinoma (OCCC), metastatic castration-resistant prostate cancer (mCRPC), NSCLC, and non-Hodgkin lymphoma (NHL). Notably, the longest progression-free survival (PFS) reported in OCCC patients was 7.4 months.

The study demonstrated favorable long-term safety and tolerability. Most treatment-emergent adverse events (TEAEs) were Grade 1-2, with no Grade 3 or higher TEAEs leading to discontinuation. Common TEAEs included fever, anemia, cytokine release syndrome, ALT/AST elevation, and decreased platelet counts.

For more research data disclosed at ESMO 2026, additional clinical trial results are available through specialized pharmaceutical databases tracking conference presentations and regulatory submissions.