BACKGROUND:EMPOWER-Lung 1 and EMPOWER-Lung 3 (phase 3 studies) demonstrated survival benefits for cemiplimab with/without chemotherapy in global (non-Japanese) patients with advanced non-small cell lung cancer (aNSCLC). This single-arm dose-expansion study assessed safety, tolerability, pharmacokinetics, and efficacy of first-line cemiplimab (350 mg intravenous every 3 weeks) as monotherapy/with chemotherapy in Japanese patients with aNSCLC. METHODS:The primary objectives were safety, tolerability, and pharmacokinetics of cemiplimab as monotherapy/with chemotherapy. Secondary objectives included immunogenicity, tumor response (objective response rate [ORR], and duration of response [DOR]). Patients whose tumors expressed programmed cell death-ligand 1 (PD-L1) ≥50% on tumor cells received cemiplimab monotherapy (Cohort A; n = 60, safety; n = 50, efficacy). Patients whose tumors expressed any level of PD-L1 received cemiplimab plus four cycles of chemotherapy (Cohort C; n = 50). RESULTS:Safety results were generally consistent with the known safety profile of cemiplimab. Treatment-emergent adverse events (grade ≥3) were experienced by 51.7% (31/60) in patients receiving cemiplimab monotherapy (Cohort A) and 68.0% (34/50) in those receiving cemiplimab + chemotherapy (Cohort C). Pharmacokinetic results were similar across both cohorts. In Cohort A patients with centrally confirmed PD-L1 ≥50%, ORR was 60.0% (30/50) with an observed DOR of 2.1-42.5 months. In Cohort C, ORR was 42.0% (21/50) with an observed DOR of 2.3-20.7 months. Immunogenicity was low in both cohorts. CONCLUSION:Cemiplimab demonstrated efficacy in Japanese patients as monotherapy for PD-L1 ≥50% and with chemotherapy irrespective of PD-L1 expression. Overall, cemiplimab demonstrated a favorable benefit-risk profile in Japanese patients.

Background The dose escalation phase of a first-in-human (FIH) study demonstrated acceptable safety and preliminary antitumor activity of fianlimab (anti-lymphocyte activation gene-3 [LAG-3]) as monotherapy and in combination with cemiplimab (anti-programmed cell death-1 [PD-1]). Here, the authors present safety and clinical activity data from the dose-expansion portion of the FIH study in patients with advanced non-small cell lung cancer (NSCLC), clear cell renal cell carcinoma (ccRCC), head and neck squamous cell carcinoma (HNSCC), and cutaneous squamous cell carcinoma (CSCC).Methods Anti-PD-1/PD-L1 naive (N) or experienced (E) patients with advanced NSCLC, ccRCC, HNSCC, and CSCC were enrolled in this phase 1 study (NCT03005782). Patients received fianlimab 1600 mg plus cemiplimab 350 mg intravenously every 3 weeks for up to 24 months. The primary end point was the objective response rate (ORR) per RECIST 1.1.Results Investigator-assessed ORR was 27% in NSCLC-N (four partial responses [PRs]), 7% in NSCLC-E (one PR), 20% in ccRCC-N (three PRs), 7% in ccRCC-E (one PR), 33% in HNSCC-N (five PRs), 7% in HNSCC-E (one PR), and 20% CSCC-E (two complete responses; one PR). The most common treatment-related treatment-emergent adverse events among patients across all cohorts were fatigue (15%), rash (12%), pruritus (10%), infusion-related reaction (10%), and adrenal insufficiency (10%).Conclusions Fianlimab plus cemiplimab demonstrated modest clinical efficacy with an acceptable safety profile in patients with advanced malignancies across several tumor types mostly in treatment-naive patients. Further investigation is warranted.

Treatment (Tx) with fianlimab (anti-LAG-3) + cemiplimab (anti-PD-1) resulted in a 57% ORR by BICR in pts with adv Mel, with an acceptable risk-benefit profile. Here, we present an efficacy analysis by BICR in subgroups of pts with adv Mel (neoadjuvant/adjuvant pretreated [NAP], elevated LDH, BRAF status, adrenal insufficiency [AI], and ctDNA status). Three independent expansion cohorts of pts who were anti-PD-(L)1 Tx-naïve for adv Mel (NCT03005782) received fianlimab 1600 mg + cemiplimab 350 mg IV every 3 weeks (wks) for ≤24 months (mos). Overall, 98 pts were enrolled (median age: 68 years). At the data cutoff (Oct 31, 2023), median follow-up was 23 mos, and median Tx duration was 36 wks. Grade ≥3 TEAEs occurred in 47% of pts, serious TEAEs in 39%, and immune-mediated AEs in 39%. Of the 76 pts (78%) who discontinued Tx, 17 discontinuations (22%) were due to TEAEs. Overall BICR-assessed median PFS (mPFS), median OS (mOS), CR rate, and ORR were 24 mos (95% CI 12-NE), NR (95% CI 42-NE), 25%, and 57% (95% CI 47-67), respectively. Estimated survival probability was 83% at 12 mos and 71% at 24 mos. A total of 31% and 4% of pts completed 1 and 2 years of Tx, respectively. In NAP pts who had received anti-PD-(L)1 Tx (n=13), the mPFS, CR rate, and ORR were NR (95% CI 1-NE), 31%, and 46% (95% CI 19-75), respectively. There were no differences in mOS in NAP pts (NR [95% CI 26-NE]) versus NAP-naïve pts (NR [95% CI 31-NE]). In NAP and NAP-naïve pts, mPFS was NR (95% CI 3-NE) and 24 mos (95% CI 12-NE), respectively. In pts with LDH > ULN (n=31), the mPFS, mOS, CR rate, and ORR were 14 mos (95% CI 4-NE), 42 mos (95% CI 23-NE), 13%, and 55% (95% CI 36-73), respectively. In pts with BRAF mutation (n=48), the mPFS, mOS, CR rate, and ORR were NR (95% CI 39-69), NR (95% CI NE-NE), 31%, and 54% (95% CI 46-70), respectively. In pts with any-grade drug-related AI (n=12), the mPFS, mOS, CR rate, and ORR were NR (95% CI 8-NE), NR (95% CI 21-NE), 58%, and 92% (95% CI 62-100), respectively. The mPFS was NR in pts with PD-L1 expression <1% (95% CI 4-NE) and ≥1% (95% CI 24-NE), and in pts with LAG-3 expression <1% (95% CI 1-NE) and ≥1% (95% CI 19-NE). The mOS was NR in pts with PD-L1 expression <1% (95% CI 23-NE) and ≥1% (95% CI NE-NE), and in pts with LAG-3 expression <1% (95% CI 12-NE) and ≥1% (95% CI NE-NE). The ORR was 50% and 71% in pts with PD-L1 expression <1% and ≥1%, and 50% and 61% in pts with LAG-3 expression <1% and ≥1%, respectively. By Day 1 of Cycle 4, ctDNA was cleared in 15/31 pts. The mOS and mPFS for pts with uncleared ctDNA was 20.8 mos and 2.6 mos, respectively. The mOS and mPFS were NR in pts who were ctDNA-negative at Wk 9. With longer follow-up, fianlimab + cemiplimab continued to demonstrate high clinical activity and a generally acceptable safety profile in subgroups of pts with adv Mel. AI was reported in 12% of pts receiving the Tx; efficacy rates were higher in pts who experienced AI than in the overall study population. Meredith McKean, Amy M. Weise, Kyriakos P. Papadopoulos, John Crown, Sajeve S. Thomas, Janice Mehnert, John M. Kaczmar, Kevin B. Kim, Nehal J. Lakhani, Melinda L. Yushak, Jayakumar Mani, Fang Fang, Shuquan Chen, Jingxiao Chen, Laura Brennan, JuAn Wang, Israel Lowy, Mark Salvati, Matthew G. Fury, Karl D. Lewis, Omid Hamid. Fianlimab + cemiplimab in patients (pts) with advanced (adv) melanoma (Mel): Subgroup analyses by blinded independent central review (BICR) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB366.

6038 Background: Concurrent blockade of LAG-3 may enhance efficacy of anti–PD-1 therapies. We present safety and clinical activity data from a Phase 1 study in patients (pts) with head and neck squamous cell carcinomas (HNSCC) treated with anti–LAG-3 (fianlimab) + anti–PD-1 (cemiplimab). Methods: Two expansion cohorts of adult pts with recurrent and/or metastatic HNSCC with no curative options who were anti–PD-1/PD-L1-naïve (cohort 11) or anti–PD-1/L1-experienced with most recent dose within 3 months (mos) prior to screening (cohort 12) were enrolled. All pts received fianlimab 1600 mg + cemiplimab 350 mg intravenously every 3 weeks (wks) for up to 24 mos. Tumor measurements were performed every 6 wks for 24 wks, then every 9 wks. Results: 15 pts each in cohort 11 and 12 (total N=30; median age: 69 years) were enrolled and treated with fianlimab + cemiplimab as of 04 Oct 2023 data cutoff.For cohorts 11 and 12 respectively, 80% and 87% of pts were male, and 53% and 80% were White. All pts had prior cancer-related systemic therapy. 33% (5/15) and 87% (13/15) of pts in cohorts 11 and 12 had ≥2 lines of prior therapies, respectively. For cohorts 11 and 12, median treatment duration was 12 wks (mean: 41 wks) and 13 wks (mean: 24 wks), and median follow-up was 12 mos and 10 mos, respectively. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 47% of pts each in cohorts 11 and 12. Serious TEAEs occurred in 13% and 20% of pts in cohorts 11 and 12, respectively. Treatment-related TEAEs (TRAEs) were reported in 67% of pts in cohorts 11 and 53% of pts in cohort 12. The most common TRAEs (any grade) were hypothyroidism (33%) in cohort 11; and fatigue (20%) and pneumonitis (20%) in cohort 12. Grade ≥3 TRAEs occurred in 7% of pts in cohorts 11 and 13% of pts in cohorts 12. Treatment-related immune-related AEs were reported in 47% and 40% of pts in cohorts 11 and 12, respectively. Treatment was discontinued due to any TEAE in 2 pts in cohort 12. In cohort 12, there was one death due to grade 5 respiratory failure attributable to aspiration pneumonia. RECIST 1.1-based investigator-assessed objective response rate (ORR) was 33% (5 partial responses [PRs]) in cohort 11 and 7% (1 PR) in cohort 12. The disease control rate (DCR) was 47% and 67% in cohorts 11 and 12, respectively. Kaplan–Meier estimation of median progression-free survival was 2 mos (95% CI, 1–14) in cohort 11 and 4 mos (95% CI, 1–7) in cohort 12 pts. Duration of responses were 17, 10, 20, 22, and 20 mos in 5 responders in cohort 11; and 32 mos in 1 responder in cohort 12. Estimated event-free probability at 12 month was 33% (95% CI, 12–56) in cohort 11 and 16% (95% CI, 3–40) in cohort 12 pts. Conclusions: Fianlimab + cemiplimab in pts with HNSCC showed signs of clinical activity with durable responses among pts with anti–PD-1/PD-L1-naïve (cohort 11) and anti–PD-1/L1-experienced (cohort 12), with an acceptable safety profile which warrants further investigation. Clinical trial information: NCT03005782 .

Analysis of T-cell subset proliferation subsequent to initiation of fianlimab as monotherapy or in combination with cemiplimab in (A) CD4 effector memory T cells and (B) CD8 effector memory T cells. Representative dot plots of CD4 and CD8+ T-cell memory subpopulations expressing Ki67+, LAG3+, HLA-DR+, PD-1+, or PD-L1+. Pharmacodynamic assay data from the 40 mg/kg dose cohort could not be generated due to poor quality of samples. DL, dose level; IV, intravenous; Q3W, every 3 weeks.

TPS9611 Background: Fianlimab (anti–lymphocyte activation gene 3 [LAG-3]) and cemiplimab (anti–programmed cell death-1 [PD-1]) are high-affinity, fully human, immunoglobulin G4 monoclonal antibodies. Concurrent LAG-3 blockade may enhance the efficacy of anti–PD-1 therapies. Relatlimab (anti–LAG-3) + nivolumab (anti–PD-1) monoclonal antibodies demonstrated benefit in progression-free survival (PFS) in advanced melanoma (Mel) patients compared with nivolumab alone in the RELATIVITY-047 study. In a multicohort Phase 1 study (NCT03005782), fianlimab + cemiplimab demonstrated reproducibly high clinical activity (objective response rate [ORR]: 61%, N=98) in three independent cohorts of advanced PD-(L)1–naïve metastatic Mel patients with an acceptable safety profile. Methods: This is a randomized, open-label, multicenter Phase 3 study (NCT06246916) comparing the fixed dose combination (FDC) of fianlimab + cemiplimab to the FDC of relatlimab + nivolumab in patients with unresectable or metastatic Mel. The primary objective is to demonstrate superiority of fianlimab + cemiplimab compared with relatlimab + nivolumab as measured by ORR assessed by blinded independent central review (BICR). This study will be conducted at approximately 80 sites across North America. Key inclusion criteria are: (1) aged ≥18 years; (2) histologically confirmed unresectable stage III or IV (metastatic) Mel; (3) no prior systemic therapy for unresectable or metastatic Mel; patients with adjuvant and/or neoadjuvant systemic therapies are eligible with a treatment-free and disease-free interval of >6 months; (4) measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1; (5) Eastern Cooperative Oncology Group performance status of ≤1; (6) adequate bone marrow, hepatic, and kidney function. Approximately 560 patients will be randomized in a 1:1 ratio to two treatment arms: Arm A: FDC of fianlimab (Dose 1) + cemiplimab (Dose 2) every 3 weeks intravenously (IV); Arm B: FDC of relatlimab 160 mg + nivolumab 480 mg every 4 weeks IV. All patients will be stratified based on metastatic stage (stage III vs M1a–b vs M1c–d), baseline lactate dehydrogenase level (≤ vs > upper limit of normal), and prior adjuvant and/or neoadjuvant systemic therapy. Patients will receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, a study withdrawal criterion is met, or the sponsor terminates the study. The primary endpoint is ORR and key secondary endpoints are PFS and overall survival. Additional secondary endpoints are duration of response, disease control rate, investigator-assessed ORR and PFS, safety, pharmacokinetics, and immunogenicity. Clinical trial information: NCT06246916 .

A, Clinical activity and (B) changes to target lesion over time in patients treated with fianlimab plus cemiplimab. Figure only includes patients who had both baseline and postbaseline target lesion assessments; not all patients had these assessments–therefore some patients may not be shown in this figure. Seven patients (7/47, 14.9%) were not evaluated in this treatment group. DL, dose level; IV, intravenous; Q3W, every 3 weeks; SOD, sum of diameters.

Summary of TEAE regardless of attribution.

A, Clinical activitya and (B) changes to target lesion over time in patients treated with monotherapy to combination therapy. aBest overall response is calculated on the basis of tumor change from the start of combination treatment. bTumor response for this patient was calculated as the best change in tumor size from the start of combination therapy. Triangles denote the last tumor assessment on fianlimab monotherapy. Figure only includes patients who had both baseline and postbaseline target lesion assessments; not all patients had these assessments—therefore some patients may not be shown in this figure. Three patients (3/16, 18.8%) were not evaluated in this treatment group. DL, dose level; IV, intravenous; Q3W, every 3 weeks; SOD, sum of diameters.

PURPOSE:Preclinical data indicate that fianlimab (antilymphocyte activation gene-3) plus cemiplimab (anti-PD-1) enhances antitumor activity. Here, we report prespecified final analyses of the dose-escalation part of a first-in-human, phase 1 study (NCT03005782) of fianlimab as monotherapy and in combination with cemiplimab in patients with advanced malignancies. PATIENTS AND METHODS:Adult patients received 1 to 40 mg/kg of fianlimab plus 350 mg of cemiplimab every 3 weeks (Q3W) across various dose-escalation schedules. Primary objectives were the rate of dose-limiting toxicities, adverse events (including immune mediated), deaths, laboratory abnormalities, and pharmacokinetics. Secondary outcomes were objective response rate, best overall response, duration of response, and antidrug antibody variables. RESULTS:Seventy-eight patients were enrolled (fianlimab + cemiplimab, n = 47; fianlimab monotherapy, n = 31). One patient treated with 3 mg/kg fianlimab + cemiplimab experienced dose-limiting toxicities, including increased blood creatine phosphokinase and myasthenic syndrome. No maximum tolerated dose was reached. Any-grade treatment-emergent adverse events occurred in 90% of patients with fianlimab monotherapy, in 87% of patients with fianlimab + cemiplimab, and in 87% of patients who transitioned from monotherapy to combination therapy. Fianlimab pharmacokinetics were dose proportional and similar in monotherapy and combination therapy. Across patients who received fianlimab + cemiplimab, five achieved a partial response, three of whom experienced a response after transitioning from monotherapy to combination therapy. Fianlimab 1,600 mg Q3W (20 mg/kg in an 80-kg individual) is the selected dose for phase 2 and phase 3 studies. CONCLUSIONS:Fianlimab as monotherapy and in combination with cemiplimab demonstrated acceptable safety and preliminary antitumor activity, which is generally consistent with previous reports of cemiplimab.

Baseline characteristics and prior therapies.

Investigator-assessed tumor response rate by Response Evaluation Criteria in Solid Tumors version 1.1.