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The combination of lenvatinib (Lenvima) and pembrolizumab (Keytruda) plus chemotherapy failed to improve overall survival (OS) vs pembrolizumab plus chemotherapy alone as frontline treatment in patients with metastatic esophageal squamous cell carcinoma (ESCC), according to data from the phase 3 LEAP-014 trial (NCT04949256) presented at the 2025 ESMO Congress.¹

The median OS in the lenvatinib arm was 17.6 months (95% CI, 15.5-19.1) vs 15.5 months (95% CI, 13.5-17.2) in the chemoimmunotherapy arm (HR, 0.92; 95% CI, 0.77-1.10; P = .1852). The 12- and 24-month OS rates were 65% and 34% in the investigational arm vs 61% and 32% in the control arm, respectively.

In patients with a PD-L1 combined positive score (CPS) of at least 10, the median OS was 18.0 months (95% CI, 16.4-20.4) in the lenvatinib arm vs 15.8 months (95% CI, 13.1-17.4) in the control arm (HR, 0.89; 95% CI, 0.71-1.11). The 12- and 24-month OS rates were 67% and 36% in the investigational arm vs 63% and 31% in the control arm, respectively.

“Lenvatinib plus pembrolizumab and chemotherapy did not significantly improve OS as first-line treatment for [patients with] metastatic ESCC vs pembrolizumab plus chemotherapy,” lead study author Jong-Mu Sun, MD, PhD, 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.

What Are the Key Components of the LEAP-014 Trial?

The LEAP-014 trial enrolled patients who were at least 18 years of age with histologically and/or cytologically confirmed locally advanced, unresectable or metastatic ESCC.² 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.¹ In the investigational arm, patients received 8 mg of oral lenvatinib once daily, plus 400 mg of intravenous (IV) pembrolizumab every 6 weeks, and either cisplatin plus 5-flourouracil (FP) or paclitaxel plus cisplatin (TP) every 3 weeks, or modified FOLFOX6 (mFOLFOX6) every 2 weeks. This was followed by 20 mg of lenvatinib plus 400 mg of pembrolizumab every 6 weeks until progression, unacceptable toxicity, or withdrawal. In the control arm, patients received 400 mg of IV pembrolizumab every 6 weeks plus FP or TP every 3 weeks or mFOLFOX6 every 2 weeks in accordance with local standards.

OS served as the primary end point. Secondary end points included progression-free survival (PFS), objective 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 (n = 423) and control (n = 427) 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 (n = 206), adverse effects (AEs; n = 72), clinical progression (n = 25), patient decision (n = 18), physician decision (n = 3), and protocol violation (n = 2). In the control arm, 23 patients completed treatment and 70 patients remained on therapy. Reasons for discontinuation included progressive disease (n = 202), AEs (n = 73), clinical progression (n = 22), patient decision (n = 25), physician decision (n = 10), and follow-up loss (n = 1).

Baseline characteristics were well balanced between the treatment groups, Sun said. Within the investigational arm, the median age was 64 (range, 27-86); 49% were above the age of 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 IVB disease. The preferred choice of chemotherapy was mFOLFOX6 (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 1 dose of study therapy. Of note, PFS and ORR were not tested for statistically significance since OS was not positive. The data cutoff for the present 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.

What Additional Efficacy Data Were Presented?

Sun stated that the OS results were consistent across the prespecified subgroups, including PD-L1 status (CPS ≥10 vs CPS <10), Region (East Asia vs North America and Western Europe vs rest of the world), and chemotherapy (FP vs TP vs mFOLFOX).

Additional results indicated that the median PFS in all randomized patients was 7.2 months (95% CI, 6.8-8.4) in the lenvatinib arm vs 6.9 months (95% CI, 5.8-7.0) in the control arm (HR, 0.89; 95% CI, 0.75-1.04). The 12- and 24-month PFS rates were 31% and 12% in the investigational arm vs 23% and 15% in the control arm, respectively.

The median PFS in patients with a PD-L1 CPS of at least 10 was 8.1 months (95% CI, 6.9-9.5) in the lenvatinib arm vs 6.9 months (95% CI, 6.3-7.2) in the control arm (HR, 0.85; 95% CI, 0.69-1.04). The 12- and 24-month PFS rates were 36% and 16% in the investigational arm vs 25% and 14% in the control arm, respectively.

With respect to response, the ORR was 62.2% (95% CI, 57.4%-66.8%) in the lenvatinib arm vs 54.8% (95% CI, 49.9%-59.6%) in the chemoimmunotherapy arm (delta, 7.3%; 95% CI, 0.7%-13.8%). In the lenvatinib arm, best responses included complete response (CR; 16.3%), stable disease (SD; 22.0%), and progressive disease (PD; 8.0%); 7.3% of patients were not evaluable (NE). In the control arm, best responses included CR (19.2%), PR (35.6%), SD (29.7%), and PD (8.9%); 5.4% of patients were NE.

The median DOR was 8.1 months (range, 1.2+ to 38.7+) in the lenvatinib arm and 17% of patients experienced a response lasting 24 months or greater. In the control arm, the median DOR was 6.8 months (range, 1.2+ to 36.4+) and 21% of patients experienced a response lasting at least 24 months.

What Were the Key Safety Data That Were Presented?

The median duration of treatment exposure was 7.1 months (range, 0.03-41.9) in the lenvatinib arm vs 5.6 months (range, 0.03-28.8) in the control arm. In the investigational arm, any-grade AEs occurred in 99.5% of patients (grade ≥3, 81.2%; grade 5, 9.7%). AEs leading to drug discontinuation occurred in 33.3% of patients. Treatment-related AEs (TRAEs) occurred in 97.1% of patients.

In the control arm, any-grade AEs occurred in 99.3% of patients (grade ≥3, 79.1%; grade 5, 11.5%). AEs leading to drug discontinuation occurred in 39.0% of patients. TRAEs occurred in 96.5% of patients.

AEs 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 AEs and infusion reactions in the experimental arm included adrenal insufficiency (any grade, 4.8%; grade ≥3, 1.4%), colitis (any grade, 1.7%; grade ≥3, 0.9%), encephalitis (any grade, 0.2%; grade ≥3, 0.2%), gastritis (any grade, 2.9%; grade ≥3, 0.2%), hepatitis (any grade, 1.2%; grade ≥3, 0.7%), hyperthyroidism (any grade, 8.1%; grade ≥3, 0%), hypophysitis (any grade, 2.1%; grade ≥3, 0.7%), hypothyroidism (any grade, 33.5%; grade ≥3, 0%), infusion reactions (any grade, 2.1%; grade ≥3, 0.5%), myocarditis (any grade, 0%; grade ≥3, 0%), myositis (any grade, 0.2%; grade ≥3, 0%), nephritis (any grade, 0%; grade ≥3, 0%), pancreatitis (any grade, 0.5%; grade ≥3, 0.5%), pneumonitis (any grade, 7.6%; grade ≥3, 2.6%), severe skin reactions (any grade, 1.9%; grade ≥3, 1.4%), thyroiditis (any grade, 0.7%; grade ≥3, 0%), type 1 diabetes mellitus (any grade, 0.5%; grade ≥3, 0.2%), and vasculitis (any grade, 0.7%; grade ≥3, 0.2%).

“Safety profiles were generally consistent with the known safety profiles of lenvatinib in combination with pembrolizumab and chemotherapy or the pembrolizumab plus chemotherapy regimen,” Sun concluded.

Disclosures: Sun reported financial interests, institutional, and research funding from MSD, Yuhan, AstraZeneca, Ono, and Pfizer.

References

1. Sun JM, Kim SB, Ogata T, et al. Lenvatinib plus pembrolizumab and chemotherapy vs pembrolizumab and chemotherapy in untreated metastatic esophageal squamous cell carcinoma: the randomized phase III LEAP-014 study. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA79.
2. Efficacy and safety of pembrolizumab (MK-3475) plus lenvatinib (E7080/​MK-7902) plus chemotherapy in participants with metastatic esophageal carcinoma (MK-7902-014/​E7080-G000-320/​LEAP-014). Clinicaltrials.gov. Updated August 22, 2025. Accessed October 17, 2025. https://clinicaltrials.gov/study/NCT04949256

An alternate regimen of docetaxel (50 mg/m² once every 2 weeks instead of 75 mg/m² once every 3 weeks) plus darolutamide (Nubeqa) and androgen deprivation therapy (ADT) demonstrated statistically highly significant and clinically meaningful improvements in grade 3–5 adverse event (AE) rates as well as grade 3–4 neutropenia or death of any reason rates in patients with metastatic hormone-sensitive prostate cancer.¹

The findings, from the phase 3 ARASAFE study (NCT05676203), were presented at the 2025 European Society for Medical Oncology Congress in Berlin, Germany by Marc-Oliver Grimm, MD, professor and chair of urology at Jena University Hospital in Jena, Germany.

By way of background, Grimm explained that the use of ADT, darolutamide, and docetaxel is FDA approved for patients with mHSPC based on findings from the phase 3 ARASENS trial (NCT027996602). In that regimen, the docetaxel dosage is 75 mg/m² once every 3 weeks. However, Grimm pointed out that toxicity such as neutropenic complications could limit the use of this regimen compared with androgen receptor pathway inhibitor/ADT doublet therapy. For ARASAFE, Grimm and his co-authors sought to evaluate toxicity in triplet therapy with darolutamide/ADT/docetaxel with docetaxel dosages of 50 mg/m² once every 2 weeks and 75 mg/m² once every 3 weeks.

“We hypothesized that triplet therapy with darolutamide, ADT, and 50 mg[/m²] every 2 weeks reduces grade 3 to 5 adverse events compared to the standard 75-mg[/m²] schedule,” Grimm said. Grimm also pointed to previous research indicating that ADT plus docetaxel 50 mg/m² once every 2 weeks was associated with better time to treatment failure and fewer grade 3–4 AEs in patients with metastatic castration-resistant prostate cancer.³

In ARASAFE, a total of 250 patients with mHSPC were randomly assigned 1:1 to darolutamide 600 mg twice daily plus ADT plus 6 cycles of docetaxel 75 mg/m² once every 3 weeks (3-week cycle, 129 patients) or to darolutamide 600 mg twice daily plus ADT plus 6 cycles of docetaxel 50 mg/m² once every 2 weeks (4-week cycle, 121 patients). Total expected docetaxel dose was 450 mg/m² in the 75 mg/m² arm vs 600 mg/m² in the 50 mg/m² arm.

Primary end points included grade 3-5 AEs and grade 3-4 neutropenia or death of any reason. Secondary end points included time to castration resistant prostate cancer, overall survival, time to pain progression, time to first symptomatic skeletal event, time to initiation of subsequent systemic antineoplastic therapy, time to worsening of disease-related physical symptoms, and quality of life.

Median age at baseline was 68.0 years (IQR, 63.0–74.0 years) in the 75 mg/m² arm vs 67.0 years (IQR, 63.0–73.0 years) in the 50 mg/m² arm. High-volume disease was present in 108 (83.7%) patients in the 75 mg/m² arm vs 104 (86.0%) patients in the 50 mg/m² arm. Mean number of docetaxel doses was 5.6 (standard deviation [SD], 1.1) in the 75 mg/m² arm vs 10.7 (SD, 2.2) in the 50 mg/m² arm. Mean cumulative docetaxel dose was 842.8 mg (SD, 181.7 mg) in the 75 mg/m² arm vs 1073.5 mg (SD, 240.4 mg) in the 50 mg/m² arm.

Grimm reported that the study reached its primary end points: The grade 3-5 AE rate was 78.9% (95% CI, 70.8%–85.6%) in the 75 mg/m² arm vs 61.2% (95% CI, 51.9%–69.9%) in the 50 mg/m² arm (P =.0024). Additionally, the grade 3–4 neutropenia/death of any reason rate was 64.1% (95% CI, 55.1%–72.3%) in the 75 mg/m² arm vs 24.0% (95% CI, 16.7%–32.6%) in the 50 mg/m² arm (P <.00001).

Grimm also reported that the rates of neutropenia, leukopenia, and febrile neutropenia favored the 50 mg/m² dosage over the 75 mg/m² dosage.

The investigators utilized prostate-specific antigen (PSA) response at week 26 as a putative surrogate for oncologic outcome. Grimm reported that the median PSA level in the 75 mg/m² arm was 0.16 ng/mL (IQR, 0.03 ng/mL–1.00 ng/mL) vs 0.26 ng/mL (IQR, 0.05 ng/mL–1.55 ng/mL) in the 50 mg/m² arm. PSA levels of 0.2 ng/mL or lower were observed in 63 (48.8%) patients in the 75 mg/m² arm vs 50 (41.3%) patients in the 50 mg/m² arm.

“In summary, ARASAFE demonstrates a statistically highly significant and clinically meaningful reduction in the incidence of grade 3 to 5 adverse event rate and the rate of grade 3 to 4 neutropenia or death regardless of reason for the experimental approach. This was achieved despite higher total doses of docetaxel in the experimental arm. Therefore, the ARASAFE approach may be considered a potential new standard of care,” Grimm said in his concluding remarks.

DISCLOSURES: Grimm noted advisory board/invited speaker/institutional associations with AstraZeneca, Bayer, Bristol Myers Squibb, Ipsen Pharma, Merck Serono, MSD, Pfizer, Roche, Eisai, Janssen Cilag, Gilead, Novartis, Telix, Astellas, Kranus, Recordati, Janssen, and Intuitive Surgical.

REFERENCES:

1. Grimm M-O, Von Amsberg G, Heers H, et al. 3-weekly docetaxel 75 mg/m2 vs 2-weekly docetaxel 50 mg/m2 in combination with darolutamide + ADT in patients with mHSPC: Results from the randomised phase III ARASAFE trial. Presented at: European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. LBA92. https://tinyurl.com/vs3p8wh3

2. FDA approves darolutamide tablets for metastatic hormone-sensitive prostate cancer. Published online August 5, 2022. Accessed October 17, 2025. https://tinyurl.com/yhjw2sw2

3. Kellokumpu-Lehtinen P-K, Harmenberg U, Joensuu T, et al. 2-weekly versus 3-weekly docetaxel to treat castration-resistant advanced prostate cancer: a randomised, phase 3 trial. Lancet Oncol. 2013;14(2):117-24. doi:10.1016/S1470-2045(12)70537-5