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Postsurgical Libtayo and placebo showed similar rates of second primary tumors in high-risk CSCC.

Among patients with high-risk cutaneous squamous cell carcinoma (CSCC), postsurgical treatment with Libtayo (cemiplimab-rwlc) has been found to be associated with a similar rate of second primary tumors (SPTs) when compared with placebo following postoperative radiotherapy, research has shown.

Findings from an analysis of the phase 3 C-POST trial were presented at the 2025 ESMO Congress in Berlin.

During the treatment period, the proportion of patients who developed at least one SPT was 11% in the Libtayo arm (209 patients) compared with 12% in the placebo arm (206 patients); during the study’s follow-up period, these rates were 8% and 7%, respectively. During the treatment period, the cumulative number of SPTs was 32 with Libtayo versus 82 for placebo, corresponding to annualized adjusted annualized SPT rates of 1.23 and 2.81, respectively. In the follow-up period, 36 total SPTs occurred in the Libtayo arm versus 41 in the placebo arm, and the annualized SPT rates were 0.72 and 1.17, respectively.

During the treatment period, 9% of patients in the Libtayo arm had one SPT, 1% had two SPTs, less than 1% had three SPTs, 0% had four SPTs, less than 1% had five SPTs and 0% had six or more SPTs. In the placebo arm, these rates were 8%, 2%, less than 1%, less than 1%, 0% and 1%, respectively. Incidence was similar during the follow-up period, with 4% of patients in each arm experiencing one SPT and less than 1% of patients falling into the multiple SPT groups within each arm.

In a post hoc analysis incorporating the first occurrence of SPTs alongside disease-free survival (DFS) events (recurrence or death), efficacy continued to favor Libtayo over placebo. The median DFS in this analysis was not reached not reached in the Libtayo group versus 21.7 months in the placebo group. At 24 months, DFS rates were 81.1% with Libtayo versus 59.1% with placebo, and this benefit was maintained over time, with rates of 73.4% versus 48.7% at 36 months and 68.4% versus 41.5% at 48 months, respectively.

“The lower number of SPTs in the Libtayo arm appeared to be driven by a small number of patients with multiple SPTs observed in the placebo arm. The robust [DFS] efficacy signal with Libtayo versus placebo was maintained in a post hoc analysis in which SPTs were included as [DFS] events,” Dr. Danny Rischin, who serves as the director of Medical Oncology at the Peter MacCallum Cancer Centre in Melbourne, Australia noted in the conclusion of his presentation.

“These prospective randomized data suggest that there may be a subset of patients who experience fewer SPTs with Libtayo, although further investigation is required.”

What Was Established in the Primary Analysis of the Trial?

With a median follow-up of 24 months, previously reported findings from the primary analysis showed that patients who received adjuvant Libtayo after surgical resection and postoperative radiotherapy achieved a median DFS that was not reached compared with 49.4 months among those treated with placebo (206 patients). The estimated 24-month DFS rates were 87.1% and 64.1%, respectively.

Based on those findings, on Oct. 8, 2025 the U.S. Food and Drug Administration (FDA) approved Libtayo for the adjuvant treatment of adult patients with CSCC at high risk of recurrence after surgery and radiation.

What Was the Design of the Trial and the Post Hoc Analysis?

The phase 3 trial is a randomized double-blind placebo-controlled study designed to evaluate adjuvant Libtayo in patients with histologically confirmed CSCC who had undergone complete resection with curative intent and completed postoperative radiotherapy. Patients were required to have high-risk features, which included nodal extracapsular extension with at least one lymph node measuring 20 mm or more, or three or more involved lymph nodes; in-transit metastases; perineural invasion; T4 lesions; or recurrent CSCC with one or more additional high-risk characteristics.

Participants were randomly assigned to receive Libtayo or placebo. In part 1 of the study, patients received Libtayo at 350 mg intravenously every three weeks for 12 weeks, followed by Libtayo at 700 mg every six weeks for an additional 36 weeks. Those in the control group received matched placebo on the same schedule. Treatment continued until completion of the planned duration, disease recurrence, or unacceptable side effects.

Patients who experienced recurrence after completing placebo treatment or after at least three months following Libtayo completion were eligible to enter an optional open-label extension phase (part 2) to receive Libtayo at 350 mg every three weeks for up to 96 weeks.

The median age of patients was 71 years in the Libtayo group and 70.5 years in the placebo group. Most patients were 65 years of age or older, representing 73% and 68% of each respective arm. The majority of participants were male (83% in both arms) and White (90% versus 92%).

Geographically, 43% of patients in the Libtayo arm and 44% in the placebo arm were enrolled from Australia or New Zealand, 18% and 15% were from North America, and 39% and 41% were from the rest of the world.

Most patients had resected high-risk tumors located in the head and neck region (79% in the Libtayo group versus 86% in the placebo group), and 21% and 14% had non–head and neck tumors, respectively. Regarding risk classification, 60% of patients in the Libtayo arm and 57% in the placebo arm were categorized as having nodal high-risk disease; 40% and 43%, respectively, had non-nodal high-risk features.

“Analysis of second primary CSCC tumors (SPTs) reported during the C-POST trial, a randomized phase 3 study of adjuvant cemiplimab vs placebo for high-risk CSCC” by Dr. Danny Rischin et al., presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract 1603MO.

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Articles

Libtayo (cemiplimab-rwlc) demonstrated a comparable rate of second primary tumors (SPTs) to placebo in high-risk cutaneous squamous cell carcinoma (CSCC) patients post-surgery and radiotherapy. The phase 3 C-POST trial revealed that Libtayo significantly improved disease-free survival (DFS) compared to placebo, with DFS rates of 81.1% versus 59.1% at 24 months. The trial design included a randomized, double-blind, placebo-controlled study with high-risk CSCC patients. The FDA approved Libtayo for adjuvant treatment in high-risk CSCC patients based on these findings.

Postsurgical Libtayo and placebo showed similar rates of second primary tumors in high-risk CSCC

Similar Incidence of Second Primary Tumors After Libtayo or Placebo for CSCC

Enhertu led to a 53% reduction in the risk of invasive disease or death versus Kadcyla in some patients with high-risk, HER2-positive breast cancer.

Among patients with high-risk, HER2-positive primary breast cancer with residual invasive disease following neoadjuvant therapy, treatment with Enhertu (fam-trastuzumab deruxtecan-nxki; T-DXd) was associated with a statistically significant and clinically meaningful improvement in invasive disease–free survival (IDFS) versus Kadcyla (ado-trastuzumab emtansine; T-DM1), clinical trial results have shown.

Interim analysis findings from the phase 3 DESTINY-Breast05 trial were presented at the 2025 ESMO Congress.

Treatment with Enhertu (818 patients) led to a 53% reduction in the risk of invasive disease or death compared with Kadcyla (817 pstients). The three-year IDFS rates were 92.4% with Enhertu versus 83.7% with Kadcyla.

Glossary:

·Invasive Disease–Free Survival (IDFS): the time a patient lives without the original cancer returning, without a new invasive cancer appearing, and without dying from any cause.

·Overall Survival (OS): the total length of time, usually measured from diagnosis or the start of treatment, that a patient is still alive.

·ECOG Performance Status (PS): a simple scale doctors use to measure how a patient's cancer is affecting their daily energy and ability to perform routine activities.

·Interstitial Lung Disease (ILD): a general term for a group of chronic lung disorders that cause inflammation and scarring of the lung tissue, which can make it hard to breathe.

·Distant Recurrence-Free Survival: the time a patient lives after treatment without the cancer coming back in a part of the body far away from the original tumor site.

·Radiation Pneumonitis: a side effect that causes inflammation and irritation of the lungs, typically occurring weeks to months after receiving radiation therapy to the chest area.

·Anemia: a common condition where the blood doesn't have enough healthy red blood cells to carry adequate oxygen from your lungs to the rest of your body, often leading to fatigue.

·Increased Aspartate Aminotransferase Levels (AST): a finding on a blood test that shows a higher-than-normal amount of the AST enzyme, which is often a sign of damage or irritation to the liver or other organs like muscle or heart.

·Increased Alanine Aminotransferase Levels (ALT): a finding on a blood test that shows a higher-than-normal amount of the ALT enzyme, which is a common indicator of liver injury or inflammation.

·Arthralgia: the medical term for pain or stiffness experienced in one or more joints, such as the knees, elbows, or wrists.

“Patients benefited [from Enhertu] irrespective of age cohorts, region of accrual, hormone receptor status, disease status at presentation, post-therapy pathologic nodal status and dual or single HER2-targeted therapy, as well as irrespective of the sequence or usage of radiation therapy for that minority of patients who did not receive [radiation] treatment,” Dr. Charles E. Geyer Jr. said in the presentation.

Geyer is a professor of medicine and chief of the Division of Malignant Hematology and Medical Oncology at the University of Pittsburgh Medical Center Hillman Cancer Center.

What Was the Rationale for DESTINY-Breast05?

Previously, the phase 3 KATHERINE trial showed that Kadcyla improved IDFS and overall survival compared with Herceptin (trastuzumab) in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant therapy. However, patients with advanced locoregional disease or positive nodal status following neoadjuvant therapy had three-year IDFS rates of 76% and 83%, respectively; the seven-year IDFS rates were 67% and 72%, respectively. These data reinforce the unmet need for improved post-neoadjuvant treatment in this population, Geyer emphasized.

This global, multicenter, randomized, open-label trial enrolled patients with residual invasive disease in the breast and/or axillary lymph nodes after neoadjuvant chemotherapy with a HER2-directed therapy. Patients needed to present with high-risk disease prior to neoadjuvant therapy, defined as inoperable early breast cancer or operable early breast cancer with axillary node–positive disease after neoadjuvant therapy. Patients also needed to have centrally confirmed HER2-positive disease and an ECOG performance status of 0 or 1. Enrolled patients were stratified by extent of disease at presentation (inoperable versus operable), type of HER2-targeted neoadjuvant therapy received (single versus dual), hormone receptor status (positive versus negative), and post-neoadjuvant therapy pathologic nodal status (positive versus negative).

Patients were randomly assigned to receive intravenous (IV) Enhertu at 5.4 mg/kg every three weeks for 14 cycles, or IV Kadcyla at 3.6 mg/kg every three weeks for 14 cycles. Treatment was followed by a 40-day safety follow-up period.

Notably, concomitant adjuvant endocrine therapy was allowed per local practice protocols. Additionally, radiotherapy, if administered, could be initiated concurrently with study therapy or completed prior to the initiation of study therapy per the investigator. An interstitial lung disease (ILD) monitoring program was required for patients who received radiotherapy.

IDFS served as the primary end point, with disease-free survival (DFS) as a key secondary end point. Other secondary end points included OS, distant recurrence–free interval (DRFI), brain metastasis–free interval (BMFI) and safety.

What Did the DESTINY-Breast05 Patient Population Look Like?

In total, 1635 patients were randomly assigned to receive Enhertu (818 patients) or Kadcyla (817 patients). In the Enhertu arm, 806 patients received treatment. A total of 27.7% of patients in this arm discontinued treatment due to side effects (17.9%), patient withdrawal (7.4%), disease recurrence (0.2%), physician decision (1.9%) and protocol deviation (0.2%). In total, 72.3% of patients in this arm completed study treatment, and the median study duration was 29.9 months.

In the Kadcyla arm, 801 patients received treatment. A total of 23.7% of patients in this arm discontinued treatment due to side effects (12.7%), patient withdrawal (6.2%), disease recurrence (3.7%), physician decision (0.6%), protocol deviation (0.1%) and other reasons (0.1%). In total, 76.3% of patients in this arm completed study treatment, and the median study duration was 29.7 months.

In the Enhertu arm, the median age was 50.3 years, Asian patients were the most predominant race (48.8%), and most patients had HER2 3+ disease by immunohistochemistry (IHC) (82.6%), hormone receptor–positive disease (71%), inoperable disease (52.7%), positive nodal status (80.7%), received dual HER2-targeted therapy with Herceptin plus Perjeta (pertuzumab) (77.9%), prior anthracycline use (51.7%) and received prior adjuvant radiotherapy (93.4%). In the Kadcyla arm, the median age was 50.6 years, Asian patients were the most predominant race (47.2%), and the highest proportions of patients had HER2 3+ disease by IHC (82.%), hormone receptor–positive disease (71.4%), inoperable disease (51.9%), positive nodal status (80.5%), received dual HER2-targeted therapy with Herceptin plus Perjeta (78.5%), prior anthracycline use (48.8%), and received prior adjuvant radiotherapy (92.9%).

What Additional Efficacy Outcomes Were Observed in DESTINY-Breast05?

Overall, investigators observed lower rates of distant and local recurrences, including central nervous system (CNS) recurrences, with Enhertu versus Kadcyla. The numbers of patients with recurrences in these respective arms were as follows:

Distant recurrence: 42 (non-CNS, 25; CNS, 17); 77 (non-CNS, 52; CNS, 25)

A DFS benefit was observed with Enhertu versus Kadcyla. The three-year DFS rates were 92.3% with Enhertu versus 83.5% with Kadcyla.

DRFI, BMFI and OS benefits were also seen with Enhertu versus Kadcyla. The respective three-year DRFI rates were 93.9% and 86.1%. The respective three-year BMFI rates were 97.6% and 95.1%. The respective three-year OS rates were 97.4% and 95.7%.

Regarding on-study treatment exposure, in the Enhertu arm, the median study treatment duration was 9.8 months, and 72.3% of patients completed the planned 14 cycles of therapy. In the Kadcyla arm, the median study treatment duration was 9.7 months, and 76.3% of patients completed the planned 14 cycles of therapy. Notably, patients who discontinued the study before receiving 14 cycles of study treatment were permitted to receive an additional HER2-targeted therapy per standard of care (SOC) guidelines to complete 14 total cycles of HER2-targeted adjuvant therapy.

What Was the Safety Profile of Enhertu vs Kadcyla in DESTINY-Breast05?

In the Enhertu arm, any-grade treatment-emergent side effects were reported in 99.5% of patients, and 50.6% of patients experienced grade 3 (severe) or higher treatment-emergent side effects. Serious treatment-emergent side effects (17.4%) and those associated with drug discontinuation (17.9%; drug-related ILD/pneumonitis, 10.8%), drug interruptions (49.6%), dose reductions (26.4%) and deaths (0.4%; ILD/pneumonitis, two patients; respiratory tract infection adjudicated as not ILD, one patient) also occurred.

In the Kadcyla arm, any-grade treatment-emergent side effects were reported in 98.4% of patients, and 51.9% of patients experienced grade 3 or higher treatment-emergent side effects. Serious treatment-emergent side effects (13.6%) and those associated with drug discontinuation (12.9%; drug-related ILD/pneumonitis, 2.5%), drug interruptions (41.1%), dose reductions (26.6%) and deaths (0.6%; leiomyosarcoma of the uterus, aneurysm, non-neutropenic sepsis, ovarian cancer and traumatic pneumothorax, one each) also occurred.

The most commonly reported treatment-emergent side effects in the Enhertu and Kadcyla arms, respectively, were nausea (71.3%; 29.3%), constipation (32.0%; 16.2%), decreased neutrophil counts (31.6%; 14.4%), vomiting (31.0%; 9.0%), decreased white blood cell counts (29.7%; 13.0%), fatigue (29.5%; 20.2%), radiation pneumonitis (28.8%; 27%), anemia (28.3%; 17.0%), increased aspartate aminotransferase levels (25.6%; 50.2%), increased alanine aminotransferase levels (23.7%; 45.3%), diarrhea (23.2%; 8.6%), decreased platelet counts (21.2%; 49.8%), decreased appetite (20.0%; 10%), headache (15.8%; 20.7%), and arthralgia (10.3%; 20.5%).

The rates of adjudicated drug-related ILD in the Enhertu and Kadcyla arms were as follows:

No differences in adjudicated drug-related ILD instances were observed based on adjuvant radiotherapy timing (sequential or concurrent). Investigators observed similar distributions of any-grade adjudicated drug-related ILD events with sequential (Enhertu arm, 10.7%; Kadcyla arm, 2.6%) and concurrent (9.6%; 1%) radiotherapy.

The rates of left ventricular dysfunction in the Enhertu and Kadcyla arms were as follows:

“Adjuvant [Enhertu] demonstrated superior efficacy with manageable safety in patients with high-risk, HER2-positive early breast cancer and residual invasive disease after neoadjuvant therapy, which represents a potential new SOC in this post-neoadjuvant setting,” Geyer concluded.

“Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (pts) with high-risk human epidermal growth factor receptor 2–positive (HER2+) primary breast cancer (BC) with residual invasive disease after neoadjuvant therapy (tx): interim analysis of DESTINY-Breast05,” Dr. Charles E. Geyer et al., presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA1.

Kadcyla. Prescribing information. Genentech; revised May 2025; https://www.gene.com/download/pdf/kadcyla_prescribing.pdf

Enhertu (fam-trastuzumab deruxtecan-nxki) demonstrated a significant improvement in invasive disease-free survival (IDFS) compared to Kadcyla (ado-trastuzumab emtansine) in patients with high-risk, HER2-positive primary breast cancer with residual invasive disease post-neoadjuvant therapy. The DESTINY-Breast05 trial showed a 53% reduction in the risk of invasive disease or death with Enhertu. Enhertu's efficacy was consistent across various patient subgroups, and it showed benefits in disease-free survival, distant recurrence-free interval, and overall survival. Enhertu's safety profile was manageable, with notable side effects including interstitial lung disease.

Enhertu Reduces Risk of Invasive Disease or Death in HER2+ Breast Cancer

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.

What Are the Key Components of the Trial?

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.

What Additional Efficacy Data Were Presented?

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.

What Were the Key Safety Data That Were Presented?

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.

“Lenvatinib Plus Pembrolizumab and Chemotherapy Versus Pembrolizumab and Chemotherapy in Untreated Metastatic Esophageal Squamous Cell Carcinoma” by Dr. Jong-Mu Sun, et al., ESMO Congress 2025.

“Efficacy and Safety of Pembrolizumab Plus Lenvatinib Plus Chemotherapy in Participants With Metastatic Esophageal Carcinoma” by Dr. Jong-Mu Sun, et al., ClinicalTrials.gov.

The combination of Lenvima (lenvatinib) and Keytruda (pembrolizumab) with chemotherapy did not significantly improve overall survival (OS) in patients with metastatic esophageal squamous cell carcinoma (ESCC) compared to Keytruda and chemotherapy alone. The median OS was slightly higher in the Lenvima arm, but not statistically significant. Progression-free survival (PFS) and overall response rate (ORR) showed modest improvements. Safety profiles were consistent with known data, with high rates of side effects in both treatment arms. The study involved 850 patients, with balanced baseline characteristics.

Lenvima Combo Fails to Extend Survival in Esophageal Cancer

For patients with MET exon 14-altered NSCLC, Tepmetko was associated with frequent side effects, although the safety profile is considered manageable.

Among patients with MET exon 14-altered non-small cell lung cancer (NSCLC), treatment with Tepmetko (tepotinib) was associated with a high frequency of side effects, although the safety profile is considered manageable, according to a pooled safety analysis of cohorts A and C of the phase 2 VISION trial.

Notably, these findings were consistent with prior reports from the trial. In the pooled safety analysis of cohorts A and C (313 patients), any-grade side effects occurred in 99% of patients, and grade 3 (severe) or higher side effects were reported in 68.4% of patients. Treatment-related side effects were observed in 91.7% of patients, including grade 3 or higher in 36.1% of patients. Any-grade serious side effects and serious treatment-related side effects occurred in 54.6% and 16% of patients, respectively. Side effects led to dose reductions in 33.2%, treatment interruptions in 43.8% and permanent discontinuation in 15.7% of patients. These rates of treatment-related side effects were 33.2%, 43.8% and 15.7%, respectively. Additionally, 13.7% of patients experienced a side effect that led to death, three of which were treatment related.

The most common treatment-related side effects included peripheral edema (any-grade, 67.7%; grade 3 or higher, 11.8%), hypoalbuminemia (25.2%; 3.8%), nausea (23.3%; 0.6%), diarrhea (22.7%; 0.3%), increased blood creatinine levels (22.0%; 1.3%), alanine aminotransferase (ALT) level elevation (14.1%; 2.2%), decreased appetite (11.5%; 0.3%), aspartate aminotransferase level elevation (11.2%; 1.9%) and amylase level increase (10.5%; 1.9%).

Peripheral edema: swelling of the extremities.

Hypoalbuminemia: low levels of albumin in the blood.

Alanine aminotransferase (ALT) level elevation: an indication of liver damage.

Aspartate aminotransferase level elevation: an indication of liver or muscle damage.

Pleural effusion: accumulation of fluid between the lungs and the chest wall.

ECOG performance status: a method of measuring patients’ ability to complete daily tasks, with lower scores indicating greater independence.

In total, 37.4% of patients required at least one dose reduction. The most common any-grade treatment-related side effect leading to dose reduction, treatment interruption and treatment discontinuation was peripheral edema (15.3%, 18.8%, and 6.1% of patients, respectively). Other treatment-related side effects leading to dose reductions were generalized edema (3.2%), edema (2.2%), pleural effusion (1.6%), increased blood creatinine levels (2.6%), hypoalbuminemia (1.3%), fatigue (1.0%), asthenia (1.0%) and localized edema (1.0%). Other treatment-related side effects leading to treatment interruptions included increased blood creatinine levels (5.8%), generalized edema (4.8%), edema (3.5%), pleural effusion (3.2%), increased ALT levels (2.6%), localized edema (2.2%) and nausea (2.2%). Other treatment-related side effects leading to treatment discontinuation included edema (1.3%), generalized edema (1.0%), pleural effusion (1.0%), interstitial lung disease (1.0%) and pneumonitis (1.0%).

Additionally, health-related quality of life (HRQOL) patient-reported outcome (PRO) scores remained stable with Tepmetko use. Investigators observed no meaningful change in European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) or EuroQol 5-Dimension 5-Level (EQ-5D-5L) scores up to 228 weeks. At the end of treatment, among patients evaluated for HRQOL, the mean change from baseline for the EORTC QLQ-C30 global health status (GHS) was –7.1 and the mean change for the EuroQol visual analogue scales (EQ-VAS) was –10; positive values signified improvement. The mean changes from baseline in the EORTC QLQ-lung cancer (LC13) symptom scores for cough, dyspnea and chest pain, respectively, were –6.1, 7.1 and –2.3; negative values signified improvement. Furthermore, the median time to deterioration of the EORTC QLQ-LC13 symptom scores for cough, chest pain, and dyspnea were 36.5 months, 30.4 months and 5.5 months, respectively.

“Throughout the VISION trial, patients completed questionnaires evaluating their QOL before and while receiving [Tepmetko],” Dr. Enriqueta Felip, lead study author and head of the Thoracic Cancer Unit at Hospital Universitari de la Vall d'Hebron in Barcelona, Spain, and coauthors explained in the conclusion of the poster presentation. “Overall, patients reported that health and QOL remained stable while receiving [Tepmetko]. Specific scores relating to symptoms experienced by patients with lung cancer were improved during treatment for symptoms such as cough and chest pain and remained stable for shortness of breath.”

What Was the Design of the VISION Trial of Tepmetko in Patients With 

The VISION trial was a single-arm study evaluating Tepmetko in patients with advanced NSCLC harboring MET exon 14 skipping alterations.The study evaluated Tepmetko at a dose of 500 mg orally once daily and comprised three cohorts.

Eligible patients were at least 18 years of age, had histologically or cytologically confirmed NSCLC with MET exon 14 skipping alterations detected by liquid biopsy and/or tissue biopsy, measurable disease and an ECOG performance status of 0 or 1. Prior immunotherapy was permitted.

Patients were excluded if their tumors harbored EGFR mutations or ALK rearrangements, if they had received more than two prior lines of systemic therapy, or if they had prior exposure to MET or HGF inhibitors.

What Were the Baseline Patient Demographics in the VISION NSCLC Trial?

The median age of patients with MET exon 14 skipping NSCLC was 72 years. In total, 50.8% of patients were female, 73.8% of patients had an ECOG performance status of 1 and 47.6% of patients had received prior treatment.

At study entry, 47.6% of patients had received at least one prior systemic therapy. The median treatment duration was 7.5 months and 19 patients remained on Tepmetko for at least 48 months.

Felip E, Ferrara R, Veillon R, et al. Safety and patient-reported outcomes with tepotinib in patients with 

ex14 skipping NSCLC: ≥3 years follow-up of VISION. Presented at: 2025 IASLC World Conference on Lung Cancer; September 6-10, 2025; Barcelona, Spain. Poster P3.12.40.

Tepotinib phase II in NSCLC harboring MET alterations (VISION). ClinicalTrials.gov. Updated August 14, 2025. Accessed September 9, 2025. https://www.clinicaltrials.gov/study/NCT02864992

Tepmetko (tepotinib) treatment in MET exon 14-altered NSCLC patients showed a high incidence of side effects, with 99% experiencing any-grade side effects and 68.4% facing severe ones. Treatment-related side effects were common, leading to dose reductions, interruptions, or discontinuations. Despite these, health-related quality of life scores remained stable, with some symptom improvements. The VISION trial, a single-arm study, evaluated Tepmetko in patients with advanced NSCLC, excluding those with EGFR mutations or ALK rearrangements. The median patient age was 72, with a median treatment duration of 7.5 months.

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