Phase I Study of Fianlimab, a Human Lymphocyte Activation Gene-3 (LAG-3) Monoclonal Antibody, in Combination With Cemiplimab in Advanced Melanoma

Abstract

PURPOSE

Coblockade of lymphocyte activation gene-3 (LAG-3) and PD-1 receptors could provide significant clinical benefit for patients with advanced melanoma. Fianlimab and cemiplimab are high-affinity, human, hinge-stabilized IgG4 monoclonal antibodies, targeting LAG-3 and PD-1, respectively. We report results from a first-in-human phase-I study of fianlimab and cemiplimab safety and efficacy in various malignancies including advanced melanoma.

METHODS

Patients with advanced melanoma were eligible for enrollment into four cohorts: three for patients without and one for patients with previous anti–PD-1 therapy in the advanced disease setting. Patients were treated with fianlimab 1,600 mg and cemiplimab 350 mg intravenously once every 3 weeks for up to 51 weeks, with an optional additional 51 weeks if clinically indicated. The primary end point was objective response rate (ORR) per RECIST 1.1 criteria.

RESULTS

ORRs were 63% for patients with anti–PD-1–naïve melanoma (cohort-6; n = 40; median follow-up 20.8 months), 63% for patients with systemic treatment–naïve melanoma (cohort-15; n = 40; 11.5 months), and 56% for patients with previous neo/adjuvant treatment melanoma (cohort-16; n = 18, 9.7 months). At a median follow-up of 12.6 months for the combined cohorts (6 + 15 + 16), the ORR was 61.2% and the median progression-free survival (mPFS) 13.3 months (95% CI, 7.5 to not estimated [NE]). In patients (n = 13) with previous anti–PD-1 adjuvant therapy, ORR was 61.5% and mPFS 12 months (95% CI, 1.4 to NE). ORR in patients with previous anti–PD-1 therapy for advanced disease (n = 15) was 13.3% and mPFS 1.5 months (95% CI, 1.3 to 7.7). Treatment-emergent and treatment-related adverse events ≥grade 3 (G3) were observed in 44% and 22% of patients, respectively. Except for increased incidence of adrenal insufficiency (12%-G1-4, 4%-G3-4), no new safety signals were recorded.

CONCLUSION

The current results show a promising benefit-risk profile of fianlimab/cemiplimab combination for patients with advanced melanoma, including those with previous anti–PD-1 therapy in the adjuvant, but not advanced, setting.

INTRODUCTION

Globally, 324,635 new cases of cutaneous melanoma were diagnosed in 2020, with an estimated mortality of 57,043 people.¹ The global incidence of cutaneous melanoma is on the rise, with a projected 50% increase by 2040.² Of patients newly diagnosed with cutaneous melanoma, approximately 10% have an advanced metastatic disease associated with a 5-year survival rate of approximately 25%.^3,4 Clinical features such as elevated serum lactate dehydrogenase (LDH) levels and presence of hepatic metastases are associated with a poorer prognosis.^4,5

CONTEXT

• Key Objective

• We report novel data of clinical benefit (response rate, progression-free survival [PFS]) with coblockade of lymphocyte activation gene-3 (LAG-3; fianlimab) and PD-1 (cemiplimab) for advanced melanoma.

• Knowledge Generated

• In advanced melanoma, fianlimab/cemiplimab yielded the highest LAG-3/PD-1 efficacy and durability possibly related to increased LAG-3 exposure, objective response rate 61.2% and median PFS 13.3 months, with safety comparable with anti–PD-1 monotherapy except increased adrenal insufficiency. Clinical benefit was similar to that observed with cytotoxic T-lymphocyte–associated antigen-4/PD-1. Novel data in patients with previous adjuvant anti–PD-1 exposure showed similar efficacy, the strongest data to date in this population with need.

• Relevance (G.K. Schwartz)

• The combination of fianlimab and cemiplimab shows promising clinical activity in patients with advanced melanoma with a reasonable safety profile and may represent a future treatment option. Its ultimate place in cancer medicine for patients with advanced melanoma will depend though on the outcome of ongoing randomized clinical trials.*

• *Relevance section written by JCO Associate Editor Gary K. Schwartz, MD, FASCO.

The approval of immune checkpoint inhibitors (ICIs) has significantly improved the prognosis of patients with advanced melanoma, producing significant response rates and durable remissions in all subsets of patients.⁶ Single-agent therapy with monoclonal antibodies (mAb) targeting the PD-1 receptor yields an overall response rate (ORR) of 35%-45%, a median progression-free survival (mPFS) of 6.6-6.9 months, and a median overall survival (OS) of approximately 37 months.^7-9 All efficacy parameters are improved over anti–PD-1 monotherapy with the approved combination of the anti–PD-1 agent nivolumab plus the anti–cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4) ipilimumab, but this comes at the cost of significantly heightened immune-related toxicity, highlighting the need for novel combinations with a favorable safety profile.^10-12

Lymphocyte activation gene-3 (LAG-3) is a type I transmembrane protein that binds to the major histocompatibility complex (MHC) class II protein.¹³ Similar to CTLA-4 and PD-1, LAG-3 is an ICI selectively expressed on activated immune cells including CD4+ and CD8+ T cells.¹⁴ LAG-3 is observed to coexpress with PD-1 on tumor-infiltrating CD4+ and CD8+ T cells in multiple preclinical tumor models as well as in multiple human tumors including melanoma.^13,15-17 Moreover, coblockade of LAG-3 and PD-1 exert synergistic antitumor effects in various preclinical models of cancer, including melanoma¹⁵ and PD-1–resistant tumors.¹⁸ These data suggest that coblockade of LAG-3 and PD-1 receptors could provide significant clinical benefit for patients with advanced melanoma. Indeed, coblockade of LAG-3 and PD-1 was associated with significantly longer PFS compared with anti–PD-1 monotherapy in the RELATIVITY-047 phase II/III trial comparing nivolumab and relatlimab fixed-dose combination with nivolumab alone, leading to FDA approval of this combination for patients with advanced melanoma.¹⁹

Fianlimab (REGN3767) and cemiplimab are both high-affinity, human, hinge-stabilized IgG4 mAb. Cemiplimab blocks interactions of PD-1 with PD-L1/PD-L2.²⁰ Fianlimab blocks LAG-3/MHC class II–driven T-cell inhibition.²¹ In a murine model (MC38 mouse colon carcinoma), the combination of cemiplimab and fianlimab induced significant tumor regression and an increase in OS that was far more pronounced than either antibody on its own.²¹ In November 2016, we launched a phase-I first-in-human clinical trial to assess the safety and clinical activity of fianlimab monotherapy and fianlimab combination with cemiplimab as treatment for multiple tumor types. The primary objectives for the escalation phase were to assess the safety and pharmacokinetics (PK) of fianlimab monotherapy and fianlimab combination with cemiplimab for the treatment of advanced malignancies. Escalation cohorts revealed fianlimab alone and its combination with cemiplimab had an acceptable safety profile that was comparable with that previously reported for cemiplimab and other ICIs, thus suggesting that fianlimab combination with cemiplimab could provide a combination checkpoint blockade for the treatment of advanced malignancies.²² Fianlimab concentrations increased in a dose-dependent manner and were unaffected by coadministration with cemiplimab, nor did fianlimab affect the cemiplimab PK.²² The recommended fianlimab dose for the expansion cohorts was determined to be 20 mg/kg or 1,600 mg fixed-dose equivalent once every 3 weeks as monotherapy and in combination with cemiplimab.

Here, we report on the four expansion cohorts of fianlimab in combination with cemiplimab that enrolled patients with advanced melanoma.

METHODS

Study Design

This study was an open-label, nonrandomized, parallel cohort assignment, phase I clinical trial (ClinicalTrials.gov identifier: NCT03005782) conducted at 43 centers in the United States, United Kingdom, Ireland, South Korea, and Australia. In the cohort expansion part of this study, patients with six tumor types (melanoma, non–small cell lung cancer, head-and-neck squamous cell carcinoma, renal cell carcinoma, diffuse large B-cell lymphoma, and cutaneous squamous-cell carcinoma) with either PD-(L)1–naïve or PD-(L)-1–experienced disease were enrolled in 16 cohorts.

The study was executed in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. The study protocol and all amendments were approved by the institutional review board or independent ethics committee at each participating site and are available in the Data Supplement (online only). All authors reviewed the data for accuracy and collaborated in the preparation of the manuscript.

Participants

Patients with advanced melanoma were enrolled into four expansion cohorts (6, 7, 15, and 16; Data Supplement, Fig S1) and all had unresectable locally advanced (stage III) or metastatic (stage IV) melanoma, with at least one measurable lesion according to RECIST 1.1.²³ Patients had to be age 18 years and older, have an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ and bone marrow function. Patients enrolled into cohorts 6 and 15 were anti–PD-1–naïve, but patients in cohort 6 could have received one previous line of therapy (excluding anti–PD-1/PD-L1) for metastatic melanoma. Enrollment into cohort 15 started after completion of enrollment into cohort 6. Patients in cohort 16 had to have received systemic treatment in the adjuvant or neoadjuvant setting with a treatment-free and disease-free interval >6 months but be treatment-naïve for advanced disease. Patients in cohort 7 had to have received an anti–PD-1 therapy for advanced melanoma with the most recent dose within 3 months before screening.²⁴ Patients with acral lentiginous and mucosal melanomas were eligible but their combined number was limited to <15% of patients enrolled in each cohort. Key exclusion criteria included uveal melanoma and previous treatment with LAG-3–targeting agents. Small molecule treatment and radiation therapy within 2 weeks, or active brain metastases, were not allowed. The full protocol is available online. All participants provided written informed consent before enrollment.

Procedures

Patients received sequential fixed-dose intravenous fianlimab 1,600 mg and cemiplimab 350 mg as a 30-minute infusion each, once every 21 days (cycle) for up to 17 cycles (ie, 51 weeks). Treatment continued until completion of the 51-week treatment period, disease progression, unacceptable toxicity, withdrawal of consent, or until study withdrawal criterion was met. Optional treatment continuation for an additional 51 weeks was available at the investigator's discretion after consultation with the sponsor in case of evidence of clinical benefit. A 24-week follow-up period ensued after completion of the initial or additional treatment period. Follow-up consisted of seven visits, the first at 18-24 days after the last cycle-visit and then once every 28 ± 7 days.

Radiologic tumor assessments occurred every 6 weeks for the first 24 weeks, then every 9 weeks for the subsequent 27 weeks, regardless of delays in dosing of study drugs, and every 9 weeks during the 24-month follow-up period. Tumor responses were assessed locally by the trial site in accordance with RECIST 1.1 criteria.²³ Formalin-fixed, paraffin-embedded baseline tumor samples were used to determine LAG-3 and PD-L1 expression levels by immunohistochemistry (Data Supplement).

Multiplex immunohistochemistry was used to determine CD3+, CD4+, and CD8+ density in tumor area before and during fianlimab + cemiplimab combination treatment (Data Supplement).

The pharmacokinetic analysis set included all patients who received any study drug and who had at least one nonmissing concentration result after the first dose of study drug (Data Supplement).

Safety evaluations were conducted at each dosing visit and at additional visits during the first 28 days of therapy. Adverse events and laboratory abnormalities were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03.

Outcomes

The primary objective was to assess the preliminary antitumor activity of fianlimab in combination with cemiplimab as measured by ORR per RECIST 1.1 assessed by the investigators.²³ Secondary objectives included duration of response (DOR), PFS, safety, and PK of fianlimab in combination with cemiplimab.

Statistical Analysis

The sample size calculated for cohorts 6 and 7 was 25 and 27 patients, respectively, on the basis of a Simon 2-stage Minimax design with one-sided significant level of 5% and power of 80%. Additional patients could be enrolled in both cohorts 6 and 7 at the discretion of the sponsor and the investigators up to a maximum of 40 patients if clinically meaningful activity was observed. The null hypothesis (H0) was overall response of 30% or less (cohort 6) and 5% or less (cohort 7), versus an alternative hypothesis (H1) of a response rate of 55% or greater (cohort 6) and 20% or greater (cohort 7). Enrollment into cohort 15 and cohort 16 did not follow a Simon 2-stage design, rather 15 patients were initially enrolled as this sample size was expected to yield sufficient estimates of preliminary efficacy and safety, with up to 25 additional patients enrolled at the discretion of the sponsor and the investigators. The safety analysis set included all patients who received any study drug and was used for analysis of all clinical safety and efficacy variables. Categorical and continuous data were summarized with frequencies and percentages or descriptive statistics, respectively. Clopper-Pearson exact CI test was used to generate 95% CIs for ORR and disease control rate. PFS rates were estimated using Kaplan-Meier (KM) analysis.

RESULTS

A total of 113 patients with advanced melanoma were enrolled in four expansion cohorts between October 16, 2018, and April 7, 2022 (data cutoff date November 1, 2022). Enrollment was completed as planned in cohorts 6 and 15 with 40 patients with anti–PD-1–naïve melanoma in each cohort, while 18 of 40 planned patients were enrolled in cohort 16. Thirteen of the 18 patients enrolled into cohort 16 had previous adjuvant anti–PD-1 therapy. Fifteen patients who had previously received an anti–PD-1 therapy for advanced disease were enrolled into cohort 7. Because of a lower than anticipated response rate in this initial group of patients, the sponsor elected not to proceed to stage II of the Simon design in Cohort 7 to maximize benefit to patients. Patients' disposition, demographics, and baseline characteristics are shown in Table 1 and the Data Supplement (Tables S1 and S2).

TABLE 1.

Patients' Demographics and Baseline Characteristics

Characteristic	Cohort 6—Anti–PD-1–Naïve (n = 40)	Cohort 15—Systemic Treatment–Naïve (n = 40)	Cohort 16—Previous Neo/Adjuvant Treatment (n = 18)	No Previous Anti–PD-1 Treatment for Advanced Melanoma (n = 98)
Age, years
Median (IQR), years	69.5 (55.0-76.5)	69.0 (57.5-76.5)	60.5 (50.0-70.0)	68.0 (55.0-75.0)
≥65, No. (%)	24 (60.0)	25 (62.5)	8 (44.4)	57 (58.2)
Male, No. (%)	25 (62.5)	23 (57.5)	11 (61.1)	59 (60.2)
White, No. (%)	36 (90.0)	36 (90.0)	16 (88.9)	88 (89.8)
Melanoma subtype, No. (%)
Acral	3 (7.5)	2 (5.0)	0	5 (5.1)
Mucosal	1 (2.5)	0	0	1 (1.0)
Cutaneous nonacral	23 (57.5)	17 (42.5)	8 (44.4)	48 (49.0)
Missing	13 (32.5)	21 (52.5)	10 (55.6)	44 (44.9)
BRAF mutant, No. (%)	11 (27.5)	12 (30.0)	7 (38.9)	30 (30.6)
Metastatic status at baseline, No. (%)
M0	5 (12.5)	1 (2.5)	4 (22.2)	10 (10.2)
M1a	32 (80.0)	35 (87.5)	10 (55.6)	77 (78.6)
M1c	19 (47.5)	10 (25.0)	6 (33.3)	35 (35.7)
Unknown/missing	1 (2.5)	2 (5.0)	0	3 (3.1)
Baseline tumor burden,b mm, median (IQR)	51 (29-101)	52 (26-82)	40 (13-79)	49 (25-81)
Liver metastases, No. (%)	14 (35.0)	4 (10.0)	2 (11.1)	20 (20.4)
LDH level, No. (%)
>ULN	17 (42.5)	12 (30.0)	3 (16.7)	32 (32.7)
>2 × ULN	4 (10.0)	2 (5.0)	0	6 (6.1)
LDH >ULN and M1c	12 (30.0)	3 (7.5)	2 (11.1)	17 (17.3)
LAG-3 expression, No. (%)
<1%	5 (12.5)	7 (17.5)	2 (11.1)	14 (14.3)
≥1%	27 (67.5)	19 (47.5)	9 (50.0)	55 (56.1)
Unknown/missing	8 (20.0)	14 (35.0)	7 (38.9)	29 (29.6)
PD-L1 expression, No. (%)
<1%	16 (40.0)	18 (45.0)	7 (38.9)	41 (41.8)
≥1%	18 (45.0)	4 (10.0)	4 (22.2)	26 (26.5)
Unknown/missing	6 (15.0)	18 (45.0)	7 (38.9)	31 (31.6)
Any previous systemic therapy, No. (%)	8 (20.0)	0	18 (100)	26 (26.5)
Adjuvant	5 (12.5)	0	15 (83.3)	20 (20.4)
Anti–PD-1c	0	0	13 (72.2)	13 (13.3)
Otherc	5 (12.5)	0	6 (33.3)	11 (11.2)
Interferon alfa-2b	1	—	1	2
Interferon	1	—	0	1
BRAF/MEK inhibitors	1	—	4	5
Vaccine	0	—	1	1
Anti–CTLA-4	2	—	0	2
Neoadjuvant (vaccine)	0	0	1 (5.6)	1 (1.0)

Abbreviations: CTLA-4, cytotoxic T-lymphocyte–associated antigen-4; LAG-3, lymphocyte activation gene-3, LDH, lactate dehydrogenase; n, number; ULN, upper limit of normal.

^a M1a, b, or c.

^b Sum of diameters of target lesion.

^c The same patient could have had both anti–PD-1 and other adjuvant therapy.

Efficacy results are summarized in Table 2 and Figures 1 and 2. In patients with PD-(L)1–naïve melanoma (cohorts 6 and 15), ORRs were 63% and 63% (95% CI, 46 to 77 and 46 to 77), with CR rates of 15% and 13%, and PR rates of 48% and 50%, respectively. In patients with previous exposure to any (neo)adjuvant therapy (cohort 16), ORR was 56% (95% CI, 31 to 79), with complete response (CR) and partial response (PR) rates of 6% and 50%, respectively. For the combined three cohorts of patients without previous anti–PD-1 therapy for advanced disease (n = 98), ORR was 61.2% (12 CRs [12%]; 48 PRs [49%]) and KM estimate of median PFS was 13.3 months (95% CI, 7.5 to NE). At a median follow-up of 12.6 months (IQR, 8.6-19), median DOR was not reached (NR) in any of these three cohorts.

TABLE 2.

Tumor Response

Outcome	Cohort 6—Anti–PD-(L)1–Naïve (n = 40)	Cohort 15—Systemic Therapy–Naïve (n = 40)	Cohort 16—Previous Neo/Adjuvant Therapy (n = 18)	No Previous Anti–PD-1 Therapy for Advanced Melanoma (n = 98)
Median follow-up (IQR), months	20.8 (11.2-30.8)	11.5 (8.9-13.9)	9.7 (4.8-14.1)	12.6 (8.6-19.0)
Treatment exposure, median (IQR), weeks	37.1 (19.5-81.0)	35.1 (15.1-51.2)	22.9 (12.0-37.1)	32.9 (15.0-53.7)
ORR, No. (%)	25 (62.5)	25 (62.5)	10 (55.6)	60 (61.2)
95% CI for ORR	45.8 to 77.3	45.8 to 77.3	30.8 to 78.5	50.8 to 70.9
KM estimated duration of response, median (95% CI), months	NR (11.9 to NE)	NR (NE to NE)	NR (6.2 to NE)	NR (22.6 to NE)
DCR, No. (%)	32 (80.0)	32 (80.0)	12 (66.7)	76 (77.6)
95% CI for DCR	64.4 to 90.9	64.4 to 90.9	41.0 to 86.7	68.0 to 85.4
Best overall response
Complete response, No. (%)	6 (15.0)	5 (12.5)	1 (5.6)	12 (12.2)
Partial response, No. (%)	19 (47.5)	20 (50.0)	9 (50.0)	48 (49.0)
Stable disease, No. (%)	7 (17.5)	7 (17.5)	2 (11.1)	16 (16.3)
Progressive disease, No. (%)	6 (15.0)	6 (15.0)	5 (27.8)	17 (17.3)
Not evaluated,a No. (%)	2 (5.0)	2 (5.0)	1 (5.6)	5 (5.1)
KM estimated progression free survival, median (95% CI), months	24.0 (4.2 to NE)	15.3 (6.6 to NE)	11.8 (1.4 to NE)	13.3 (7.5 to NE)
Liver metastases, N1/N2 (%), ORR
Yes	6/14 (42.9)	2/4 (50.0)	0/2 (0)	8/20 (40.0)
No	19/26 (73.1)	23/36 (63.9)	10/16 (62.5)	52/78 (66.7)
Baseline LDH >ULN, N1/N2 (%), ORR
Yes	10/17 (58.8)	6/12 (50.0)	1/3 (33.3)	17/32 (53.1)
No	15/23 (65.2)	19/27 (70.4)	9/15 (60.0)	43/65 (66.2)

NOTE. Five patients had acral melanoma and one patient had mucosal melanoma. Two of the five patients with acral melanoma had their best response as PR, and one as SD. The one patient with mucosal melanoma had their best response as SD.

Abbreviations: DCR, disease control rate; KM, Kaplan-Meier; LDH, lactate dehydrogenase; n, number; NE, not estimated; NR, not reached; N1, number of patients with the listed status who had complete or partial responses; N2, number of patients with the listed status; ORR, objective response rate; SD, standard deviation; ULN, upper limit of normal.

^a There was no overall response assessment in the received data for the five subjects.

FIG 1.

Efficacy of fianlimab/cemiplimab combination in patients with no previous systemic anti–PD-1 treatment for advanced disease (cohorts 5, 15, and 16). (A) Waterfall plot showing that any tumor response was seen in 72% of patients. (B) Spider plot showing tumor responses were fast, deep, and durable in a high proportion of patients. ^aFive patients who had nonevaluable response and one more patient who only had nontarget lesion response were not included in the waterfall plot. CR, complete response; NE, not estimated; PD, progressive disease; PR, partial response; SD, stable disease; SOD, sum of diameters.

FIG 2.

Progression-free survival in all patients with no previous systemic anti–PD-1 treatment for advanced disease (cohorts 5, 15, and 16 combined). The median Kaplan-Meier estimated progression-free survival in these patients was 13 months (95% CI, 8 to non evaluated). The estimated event-free probability at 12 months was 52% (95% CI, 41 to 62). PFS, progression-free survival.

Exploratory subgroup analyses performed across these three cohorts showed that in patients with baseline LDH > upper limit of normal (n = 32), ORR was 53% (95% CI, 35 to 71), median DOR NR (95% CI, 7 to NE), and median PFS of 11.5 months (95% CI, 3.7 to NE). In patients who had liver metastasis at baseline (n = 20), ORR was 40% (95% CI, 19.1 to 63.9), median DOR 9 months (95% CI, 2.8 to NE), and median PFS 2.8 months (95% CI, 1.2 to 11.8). In patients (n = 13) who had received adjuvant therapy with an anti–PD-1 (either nivolumab or pembrolizumab), ORR was 61.5% (95% CI, 32 to 86), median DOR was NR (95% CI, 6 months to NE), and median PFS was 12 months (95% CI, 1 to NE; Data Supplement, Table S3). Median observed time to response for these three cohorts was 1.41 months (quartile 1:quartile 3, 1.38:2.73). Moreover, 65% of responders responded in <2 months, as initial tumor assessment was at 6 weeks; this means that 65% of responders had responded at their initial assessment.

Among patients who had received an anti–PD-1 therapy for advanced melanoma (cohort 7; see the Data Supplement, Table S2, for demographics and baseline characteristics), the ORR was 13.3% (two PRs; 95% CI, 1.7 to 40.5). With a median follow-up of 8 months (IQR, 1-28), median DOR was NR (95% CI, 3.4 to NE) and KM estimated median PFS was 1.5 months (95% CI, 1.3 to 7.7), consistent with previously reported results (Data Supplement, Table S4 and Fig S2).

Table 3 illustrates efficacy in patients with anti–PD-1–naïve advanced melanoma in relation to tumor expression of PD-L1 and LAG-3. A higher ORR (73% v 56%) and a longer PFS (24 [95% CI, 10 to NE] v 10 months [95% CI, 4 to NE]) were observed in patients with ≥1% (n = 26) versus <1% PD-L1 (n = 41) tumor expression. Patients with LAG-3 ≥1% (n = 55) versus LAG-3 <1% (n = 14) experienced similar ORR (64% v 57%), while PFS data were not mature enough to compare (13 months [95% CI, 8 to NE] v NR [95% CI, 1 to NE]). Notably, all patients with PD-L1 tumor expression ≥1% also had LAG-3 ≥1% (n = 26), demonstrating a complete overlap biomarker expression pattern at the minimal 1% expression cutoff, and a potential indirect association of LAG-3 biomarker with clinical efficacy because of enrichment for PD-L1 expression could not be ruled out.

TABLE 3.

Efficacy Per LAG-3 and PD-L1 Tumor Expression

LAG-3/PD-L1 Expression	Patients, n	ORR, No. (%)	DOR, Median (95% CI), Months	PFS, Median (95% CI), Months
Patients without previous anti–PD-1 treatment for advanced disease (cohorts 6 + 15 + 16)	98	60 (61.2)	NR (22.6 to NE)	13.3 (7.5 to NE)
LAG-3 expression ≥1%	55	35 (63.6)	NR (11.9 to NE)	13.3 (7.5 to NE)
LAG-3 expression <1%	14	8 (57.1)	NR (6.6 to NE)	NR (1.4 to NE)
Unknown LAG-3 expression	29	17 (58.6)	NR (NE to NE)	NR (2.8 to NE)
PD-L1 expression ≥1%	26	19 (73.1)	NR (22.6 to NE)	24.0 (9.9 to NE)
PD-L1 expression <1%	41	23 (56.1)	NR (7.3 to NE)	9.9 (4.2 to NE)
Unknown PD-L1 expression	31	18 (58.1)	NR (NE to NE)	15.3 (2.8 to NE)
LAG-3 expression ≥1% and PD-L1 expression ≥1%	26	19 (73.1)	NR (22.6 to NE)	24.0 (9.9 to NE)
LAG-3 expression ≥1% and PD-L1 expression <1%	25	14 (56.0)	NR (6.2 to NE)	7.5 (4.2 to NE)
LAG-3 expression <1% and PD-L1 expression ≥1%	0	NA	NA	NA
LAG-3 expression <1% and PD-L1 expression <1%	14	8 (57.1)	NR (6.6 to NE)	NR (1.4 to NE)

NOTE. As seen in the table: all patients with LAG-3 expression <1% also had PD-L1 expression <1%. In addition, all patients with PD-L1 expression ≥1% also had LAG-3 expression ≥1%.

Abbreviations: DOR, duration of response; LAG-3, lymphocyte activation gene-3; NA, not applicable; NE, not estimated; NR, not reached; ORR, objective response rate; PFS, progression-free survival.

Multiplex immunohistochemistry analyses showed that in tumor samples taken from cohort 6 patients (n = 39) on day 8 of cycle 2, CD3+ T-cell density increased in responders (paired Wilcoxon signed rank test P = .02) but not in nonresponders (P = .74). Similarly, the density of CD8+ T cells was significantly higher in responders than in nonresponders with treatment (Wilcoxon rank sum test P = .01; Data Supplement, Fig S3). There was no significant association of baseline tumor-infiltrating lymphocyte density by LAG-3+ or PD1+ subsets with response to treatment (Data Supplement, Fig S4).

All patients with melanoma enrolled received at least one dose of fianlimab plus cemiplimab and were included in the safety analyses (Table 4, Data Supplement, Table S5). Overall, the safety profile of fianlimab/cemiplimab combination treatment was generally consistent with the safety profile of single-agent cemiplimab and other anti–PD-(L)1 agents. In patients without previous anti–PD-1 therapy for advanced melanoma, treatment-emergent adverse events (TEAEs) were observed in 94% (any grade [G]) and 44% (≥G3), treatment-related adverse events (TRAEs) in 79% and 22%, and TE potential immune-related adverse events (irAEs) in 65% and 12% of the population, respectively. TE adrenal insufficiency was observed in 12% (any grade) and 4% (≥G3). Discontinuation due to TRAEs occurred in 13% of this population. In patients with previous anti–PD-1 therapy for advanced melanoma, TEAEs (any grade v ≥G3) were observed in 80% and 47%, TRAEs in 53% and 20%, irAEs in 33% and 13%, and TE adrenal insufficiency in 7% and 0% of the population, respectively. TRAEs leading to death occurred in two patients (2%), both in cohort 15: one treatment-related colitis/toxic megacolon and one nonrelated cardiogenic shock with concurrent COVID-19 infection and pulmonary edema. No case of myocarditis was observed.

TABLE 4.

Safety

Safety Outcome	Anti–PD-1–Naïve for Advanced Disease		Anti–PD-1–Experienced
	n = 98		n = 15
Treatment exposure, median (IQR), weeks	33 (15-54)		9 (6-14)
TEAEs, regardless of attribution, No. (%)	Any grade	Grade 3 to 5	Any grade	Grade 3 to 5
Overall	92 (93.9)	43 (43.8)	12 (80.0)	7 (46.7)
Serious	32 (32.6)	29 (29.6)	5 (33.3)	4 (26.7)
TRAEs, No. (%)
Overall	77 (78.6)	22 (22.4)	8 (53.3)	3 (20.0)
Serious	16 (16.3)	15 (15.3)	2 (13.3)	2 (13.3)
TEAEs, occurred in ≥10% of patients in either group, No. (%)
Fatigue	52 (53.1)	4 (4.1)	4 (26.7)	0
Nausea	27 (27.6)	1 (1.0)	4 (26.7)	0
Rash	20 (20.4)	0	4 (26.7)	0
Diarrhea	22 (22.4)	1 (1.0)	3 (20.0)	0
Pruritus	18 (18.4)	0	0	0
Arthralgia	17 (17.3)	0	2 (13.3)	0
Back pain	15 (15.3)	1 (1.0)	1 (6.7)	0
Headache	14 (14.3)	1 (1.0)	1 (6.7)	0
Hypothyroidism	13 (13.3)	0	0	0
Constipation	14 (14.3)	0	3 (20.0)	0
Myalgia	13 (13.3)	0	1 (6.7)	0
Cough	12 (12.2)	0	0	0
Vomiting	13 (13.3)	1 (1.0)	3 (20.0)	0
Dry mouth	15 (15.3)	0	0	0
Infusion-related reaction	12 (12.2)	0	0	0
Pyrexia	9 (9.2)	0	2 (13.3)	0
Chills	11 (11.2)	0	1 (6.7)	0
Decreased appetite	13 (13.3)	0	1 (6.7)	0
Edema peripheral	11 (11.1)	0	0	0
COVID-19	10 (10.2)	0	0	0
Dyspnea	10 (10.2)	1 (1.0)	2 (13.3)	1 (6.7)
Adrenal insufficiency	12 (12.2)	4 (4.1)	1 (6.7)	0
Urinary tract infection	8 (8.2)	4 (4.1)	2 (13.3)	1 (6.7)
Pneumonitis	7 (7.1)	0	2 (13.3)	1 (6.7)
Weight decrease (investigations)	6 (6.1)	0	2 (13.3)	0
Hypokalemia	8 (8.2)	0	2 (13.3)	0
Asthenia	1 (1.0)	0	2 (13.3)	0

Abbreviations: TEAEs, treatment-emergent adverse events; TRAEs, treatment related adverse events.

Fianlimab concentrations in serum were similar across the four cohorts of melanoma subtypes, with similar findings for cemiplimab. Fianlimab concentration-time profiles after the first dose showed a brief distribution and a monoexponential elimination. After 12 weeks of fianlimab administration (cycle 5, day 1), fianlimab exposure increased by about 2-fold (Data Supplement, Tables S6 and S7, Fig S5).

DISCUSSION

In this first-in-human study, the combination of fianlimab and cemiplimab yielded high clinical activity in patients with advanced melanoma who had not received previous anti–PD-1 therapy in the setting of advanced disease. At a median follow-up of 12.6 months for the combined three cohorts of patients without previous anti–PD-1 therapy, high ORR and prolonged DOR were seen consistently across two independent sequentially enrolled cohorts of PD-(L)-1–naïve patients as well as in patients who had relapsed after adjuvant therapy (including previous anti–PD-1), a setting where the clinical activity of anti–LAG-3/PD-1 combinations has not been prospectively evaluated. The benefit of fianlimab plus cemiplimab extended to patients with clinical features associated with poor prognosis and reduced response to immunotherapy, including hepatic metastases and elevated LDH at baseline, which represented a meaningful proportion of patients enrolled in the study.

Lack of clinical data exists regarding retreatment with anti–PD-1 monotherapy in patients with advanced melanoma previously exposed to checkpoint inhibition in the adjuvant/neoadjuvant setting. Limited prospective data indicate a low ORR (11%)²⁵ and limited PFS (4.1 months [95% CI, 2.6 to NE]), and combination immunotherapy is often suggested.²⁶ Our data show a high ORR (61.5%) and prolonged median PFS (12 months) with fianlimab plus cemiplimab in patients who received anti–PD-1 adjuvant therapy with a disease-free interval of at least 6 months. Although limited by the small number of patients analyzed, to our knowledge, this is the greatest prospective experience to date and suggests that fianlimab plus cemiplimab represent a promising standard option for patients who relapse after previous adjuvant PD-1. Given recent adjuvant approval of PD-1 in the resectable stage II/III setting and emergence of the neoadjuvant protocol, these data are invaluable.^27,28

Fianlimab/cemiplimab combination showed improved efficacy (ORR, 61.2%; PFS, 13.3 months) versus anti–PD-1 monotherapy and apparently, notwithstanding the limitations of comparisons between phase I/II and phase III clinical data, those of relatlimab/nivolumab (ORR, 43.1%; PFS, 10.1 months).^19,29 Efficacy of fianlimab plus cemiplimab was numerically higher in patients with ≥1% versus <1% PD-L1 expression but not in patients with ≥1% versus <1% LAG-3 expression, consistent with previous reports in the literature.^8,19,30 Response rates in all populations (patients with ≥1% v <1% PD-L1 expression or with ≥1% v <1% LAG-3 expression) were higher than reported with relatlimab/nivolumab combination.^19,30 Because of the observed overlap of PD-L1 and LAG-3 biomarker expression, the numerically higher efficacy in LAG-3 >1% subset may be related to enrichment of minimal PD-L1 expression needed for cemiplimab response, and not specific for efficacy of fianlimab. The higher dose of fianlimab (1,600 mg) versus that of relatlimab (160 mg) and the frequency of administration (once every 3 weeks v once every 4 weeks, respectively) might explain the efficacy difference observed in our study compared with the Relativity-047 trial.

In the small cohort of patients with melanoma previously treated with anti–PD-1 therapy for advanced disease, efficacy was limited, with an ORR of 13%. This low-response anti–LAG-3/PD-1 combination is consistent with previously reported data in this clinical setting, indicating that LAG-3 is not a predominant mechanism of acquired resistance to PD-1–targeted treatment.^31,32

The safety profile of fianlimab plus cemiplimab combination therapy was overall comparable with that previously reported for cemiplimab and other anti–PD-1 monotherapy except for the rate of adrenal insufficiency, which appeared to be higher than with monotherapy, although clinically manageable without effect on treatment duration.

Our study presents the limitations of a relatively small sample size and of an incomplete enrollment in the cohort of patients with previous exposure to adjuvant therapy. Nonetheless, the sequential enrollment and the only partial overlap of participating sites in the two independent cohorts of PD(L)-1–naïve patients are expected to have reduced the risk of meaningful selection biases among these patients.

In summary, fianlimab plus cemiplimab demonstrated significant efficacy and an acceptable safety profile as treatment for patients with advanced melanoma who had not received previous anti–PD-1 therapy for advanced disease, including patients with liver metastases, higher-than-normal levels of LDH at baseline, and previous exposure to anti–PD-1 therapy in the adjuvant setting. These data indicate a combination that continues to present low rate of grade 3/4 toxicity consistent with LAG-3/PD1 combinations along with the high response rate consistent with benefit seen with CTLA-4/PD1 combinations. These results warrant further clinical development. At the current time, OS benefit had not been shown for patients with advanced melanoma treated with LAG-3/PD1 combinations. Clearly, longer follow-up and randomized clinical trials are needed to elucidate the putative OS benefit in this population. A phase III trial (ClinicalTrials.gov identifier: NCT05352672) of fianlimab plus cemiplimab in patients with advanced melanoma who had not received previous anti–PD-1 therapy for advanced disease is ongoing, as well as an adjuvant study for patients with fully resected high-risk melanoma (ClinicalTrials.gov identifier: NCT05608291).

DATA SHARING STATEMENT

A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO.23.02172.

AUTHOR CONTRIBUTIONS

Conception and design: Meredith McKean, Nehal J. Lakhani, Mark R. Middleton, Inderjit Mehmi, Jayakumar Mani, Vladimir Jankovic, Anne Paccaly, Sheila Masinde, Glenn Kroog, Israel Lowy, Giuseppe Gullo

Financial support: Alexander I. Spira, Israel Lowy

Administrative support: Alexander I. Spira, Mark Salvati, Israel Lowy

Provision of study materials or patients: Omid Hamid, Kyriakos P. Papadopoulos, John Crown, Tae Min Kim, Dae Ho Lee, Janice Mehnert, Nehal J. Lakhani, Kevin B. Kim, Mark R. Middleton, Alexander I. Spira, Melinda Yushak, Fang Fang, Fang Wang, Nathalie Fiaschi, Sheila Masinde, Israel Lowy

Collection and assembly of data: Omid Hamid, Karl D. Lewis, Amy Weise, Meredith McKean, Kyriakos P. Papadopoulos, John Crown, Dae Ho Lee, Sajeve S. Thomas, Janice Mehnert, John Kaczmar, Nehal J. Lakhani, Kevin B. Kim, Mark R. Middleton, Guilherme Rabinowits, Alexander I. Spira, Inderjit Mehmi, Fang Fang, Jayakumar Mani, Vladimir Jankovic, Fang Wang, Nathalie Fiaschi, Laura Brennan, Anne Paccaly, Sheila Masinde, Mark Salvati, Glenn Kroog

Data analysis and interpretation: Omid Hamid, Karl D. Lewis, Meredith McKean, Kyriakos P. Papadopoulos, Tae Min Kim, John Kaczmar, Nehal J. Lakhani, Mark R. Middleton, Alexander I. Spira, Melinda Yushak, Inderjit Mehmi, Fang Fang, Shuquan Chen, Jayakumar Mani, Vladimir Jankovic, Fang Wang, Nathalie Fiaschi, Laura Brennan, Anne Paccaly, Sheila Masinde, Mark Salvati, Matthew G. Fury, Glenn Kroog, Israel Lowy, Giuseppe Gullo

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Phase I Study of Fianlimab, a Human Lymphocyte Activation Gene-3 (LAG-3) Monoclonal Antibody, in Combination With Cemiplimab in Advanced Melanoma

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