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Lenvima and Keytruda with chemo did not help patients with metastatic esophageal squamous cell carcinoma live longer than Keytruda and chemotherapy alone.
The combination of Lenvima (lenvatinib) and Keytruda (pembrolizumab) with chemotherapy did not help patients with metastatic esophageal squamous cell carcinoma live longer compared with Keytruda and chemotherapy alone, according to results from a phase 3 study presented at the 2025 ESMO Congress.
The median OS in the Lenvima arm was 17.6 months versus 15.5 months in the chemoimmunotherapy arm. The 12- and 24-month OS rates were 65% and 34% in the investigational arm versus 61% and 32% in the control arm.
In patients with a PD-L1 combined positive score (CPS) of at least 10, the median OS was 18 months in the Lenvima arm versus 15.8 months in the control arm. The 12- and 24-month OS rates were 67% and 36% in the investigational arm versus 63% and 31% in the control arm.
“Lenvatinib plus pembrolizumab and chemotherapy did not significantly improve OS as first-line treatment for patients with metastatic ESCC versus pembrolizumab plus chemotherapy,” lead study author Dr. Jong-Mu Sun, of the Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine in Seoul, Republic of Korea, stated during the presentation.
Overall survival (OS): time from treatment start or diagnosis until death from any cause.
Progression-free survival (PFS): time during and after treatment that a patient lives without cancer growing or spreading.
Duration of response (DOR): length of time a treatment keeps cancer under control after it first responds.
Overall response rate (ORR): percentage of patients whose cancer shrinks or disappears after treatment.
The trial enrolled patients at least 18 years of age with histologically or cytologically confirmed locally advanced, unresectable, or metastatic ESCC. Prior treatment, an ECOG performance status of 2 or higher, and lack of measurable disease per RECIST 1.1 criteria excluded patients from enrollment.
A total of approximately 850 patients were randomly assigned 1:1 to treatment. In the investigational arm, patients received 8 milligrams of oral Lenvima once daily plus 400 milligrams of intravenous (IV) Keytruda every six weeks and either cisplatin plus 5-fluorouracil (FP) or paclitaxel plus cisplatin (TP) every three weeks, or modified FOLFOX6 every two weeks. This was followed by 20 milligrams of Lenvima plus 400 milligrams of Keytruda every six weeks until progression, unacceptable side effects, or withdrawal. In the control arm, patients received 400 milligrams of IV Keytruda every six weeks plus FP or TP every three weeks or modified FOLFOX6 every two weeks in accordance with local standards.
OS served as the primary end point. Secondary end points included progression-free survival (PFS), overall response rate (ORR), duration of response (DOR) by blinded independent central review, and safety.
A total of 850 patients were randomly assigned to the investigational (423 patients) and control (427 patients) arms: 421 and 426 of whom were treated in the respective arms. In the investigational arm, 2 patients completed treatment and 93 patients remained on therapy. Reasons for discontinuation included progressive disease (206 patients), side effects (72 patients), clinical progression (25 patients), patient decision (18 patients), physician decision (3 patients), and protocol violation (2 patients). In the control arm, 23 patients completed treatment and 70 patients remained on therapy. Reasons for discontinuation included progressive disease (202 patients), side effects (73 patients), clinical progression (22 patients), patient decision (25 patients), physician decision (10 patients), and follow-up loss (1 patient).
Baseline characteristics were well balanced between treatment groups, Sun said. Within the investigational arm, the median age was 64; 49% were above 65. Most patients were male (78%), Asian (66%), and from East Asia (66%). ECOG performance status was 1 in 64% of cases, and most patients had a PD-L1 CPS of 10 or greater (66%). Ninety-nine percent of patients did not have brain metastases and had stage 4B disease. The preferred choice of chemotherapy was modified FOLFOX6 (65%), followed by FP (24%) and TP (10%).
Per the study design, efficacy was evaluated in all randomized patients, whereas safety was limited to all randomized patients who received at least one dose of study therapy. PFS and ORR were not tested for statistical significance since OS was not positive. The data cutoff for this analysis was May 8, 2025, at which point approximately 482 OS events had occurred, or 42 months had passed since the first participant had been randomized.
Sun stated that the OS results were consistent across prespecified subgroups, including PD-L1 status (CPS greater or equal to 10 versus CPS less than 10), region (East Asia versus North America and Western Europe versus rest of the world), and chemotherapy (FP versus TP versus modified FOLFOX).
Additional results indicated that the median PFS in all randomized patients was 7.2 months in the Lenvima arm versus 6.9 months in the control arm. The 12- and 24-month PFS rates were 31% and 12% in the investigational arm versus 23% and 15% in the control arm.
The median PFS in patients with a PD-L1 CPS of at least 10 was 8.1 months in the Lenvima arm versus 6.9 months in the control arm. The 12- and 24-month PFS rates were 36% and 16% in the investigational arm versus 25% and 14% in the control arm.
The ORR was 62.2% in the Lenvima arm versus 54.8% in the chemoimmunotherapy arm. In the Lenvima arm, best responses included complete response (16.3%), stable disease (22%), and progressive disease (8%); 7.3% of patients were not evaluable. In the control arm, best responses included complete response (19.2%), partial response (35.6%), stable disease (29.7%), and progressive disease (8.9%); 5.4% of patients were not evaluable.
The median DOR was 8.1 months in the Lenvima arm and 17% of patients experienced a response lasting 24 months or longer. In the control arm, the median DOR was 6.8 months and 21% of patients experienced a response lasting at least 24 months.
The median duration of treatment exposure was 7.1 months in the Lenvima arm versus 5.6 months in the control arm. In the investigational arm, any-grade side effects occurred in 99.5% of patients (grade 3 [severe] or higher, 81.2%; grade 5 [death], 9.7%). Side effects leading to drug discontinuation occurred in 33.3% of patients. Treatment-related side effects occurred in 97.1% of patients.
In the control arm, any-grade side effects occurred in 99.3% of patients (grade 3 or higher, 79.1%; grade 5, 11.5%). Side effects leading to drug discontinuation occurred in 39% of patients. Treatment-related side effects occurred in 96.5% of patients.
Side effects that occurred in at least 15% of patients in either arm in order of frequency were decreased neutrophil count, nausea, hypertension, diarrhea, decreased platelet count, anemia, hypothyroidism, stomatitis, decreased white blood cell count, fatigue, decreased appetite, palmar plantar erythrodysesthesia syndrome, proteinuria, aspartate aminotransferase increase, vomiting, rash, weight decrease, constipation, alanine aminotransferase increase, pyrexia, increased lipase, increased amylase, peripheral neuropathy, hypoalbuminemia, and pneumonia.
Immune-mediated side effects and infusion reactions in the experimental arm included adrenal insufficiency, colitis, encephalitis, gastritis, hepatitis, hyperthyroidism, hypophysitis, hypothyroidism, infusion reactions, myocarditis, myositis, nephritis, pancreatitis, pneumonitis, severe skin reactions, thyroiditis, type 1 diabetes mellitus, and vasculitis.
“Safety profiles were generally consistent with the known safety profiles of Lenvima in combination with Keytruda and chemotherapy or the Keytruda plus chemotherapy regimen,” Sun concluded.
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