Fianlimab Plus Cemiplimab Generates Meaningful Responses in Anti–PD-1/PD-L1–Naïve Advanced Melanoma

Omid Hamid, MD

The combination of fianlimab (REGN3767) and cemiplimab (Libtayo) demonstrated clinically meaningful activity in patients with advanced melanoma who were naïve to anti–PD-1/PD-L1 therapy, according to findings from a phase 1 trial (NCT03005782) presented at the 2022 ESMO Congress.¹

Follow-up data from a phase 1 expansion cohort (cohort 6) and a confirmatory expansion cohort (cohort 15) showed that patients with advanced melanoma without prior anti–PD-1/PD-L1 exposure who received the doublet (n = 80) achieved an objective response rate (ORR) of 63.8% (95% CI, 52.2%-74.2%), which included a complete response rate of 8.8%, a partial response (PR) rate of 55%, and a stable disease rate of 16.3%. Additionally, 15% of patients experienced disease progression, and 5% were not evaluable for response.

Cohort 7 featured patients with advanced melanoma who had prior exposure to anti–PD-1/PD-L1 therapy (n = 15), and this group experienced an ORR of 13.3% (95% CI, 1.7%-40.5%), with the 2 responders achieving a PR; 26.4% of patients in this cohort had stable disease, and 53.3% of patients experienced disease progression.

“Observed clinical activity in the anti–PD-1/PD-L1–exposed population was consistent with previous reports of anti–LAG-3 plus anti­–PD-1/PD-L1 combination treatment in this setting,” lead study author Omid Hamid, MD, of the Angeles Clinical and Research Institute, said in a presentation of the data. “The fianlimab plus cemiplimab combination demonstrated an acceptable risk/benefit profile similar to that observed with cemiplimab monotherapy and other anti–PD-1 agents.”

Expansion cohorts 6 and 15 enrolled patients with advanced melanoma without prior exposure to PD-1/PD-L1–targeted therapy, and cohort 7 included those who did have prior treatment with an anti–PD-1/PD-L1 agent. All patients were required to have metastatic or inoperable locally advanced non-uveal melanoma with at least 1 lesion measurable per RECIST v1.1 criteria. They also needed to be at least 18 years of age and have an ECOG performance status of 0 or 1. Key exclusion criteria included having received any prior treatment with a LAG-3–targeting biologic or small molecule, or radiation therapy within 2 weeks of trial enrollment.

Patients in all cohorts received 1600 mg of intravenous (IV) fianlimab plus 350 mg of IV cemiplimab every 3 weeks for up to 51 weeks. Tumor response was assessed by investigators every 6 or 9 weeks to determine ORR.

Along with the primary end point of ORR per RECIST v1.1 criteria, secondary end points included antidrug antibodies, pharmacokinetics, and safety.

Prior data from expansion cohorts 6 (n = 33) and 7 (n = 15) showed that fianlimab plus cemiplimab elicited ORRs of 66.7% (95% CI, 48.2%-82.0%) and 13.3% (95% CI, 1.7%-40.5%), respectively.2 At the 2022 ESMO Congress, Hamid shared follow-up data from the phase 1 expansion cohort, and the confirmatory expansion cohort.

Among all patients in cohorts 6 and 15, the median age was 69 years (range, 24-88), with 49% of patients aged 65 years or older; 48% of patients were male and 72% were White. The median sum of diameters of target lesions at baseline was 51.5 mm (range, 11-214). Additionally, 92.5% of patient has cutaneous nonacral melanoma, 6.2% had acral melanoma, and 1.2% had mucosal melanoma. Notably, BRAF mutations were identified in 28.8% of patients.

At baseline, 85.0% of patients had M1 disease, 33.8% had M1c disease, and 10% had stage M0 disease. Thirty-five percent of patients presented with a lactate dehydrogenase (LDH) level above the upper limit of normal (ULN), and 23.8% of patients had liver metastases. Ten percent of patients received prior systemic therapy.

At data cutoff, 10.0% of patients in cohorts 6 and 15 completed the planned treatment, 33.8% were still receiving treatment, and 56.3% discontinued treatment. Reasons from treatment discontinuation included disease progression (31.3%), adverse effects (AEs; 15.0%), patient decision (2.5%), death (3.8%), and physician decision (3.8%). The median duration of treatment exposure was 30.9 weeks (range, 2-110).

Additional data from cohorts 6 and 15 combined showed that the median duration of response (DOR) was not yet reached (NR; 95% CI, 22.6 months–not evaluable [NE]) with the doublet, and the median disease control rate (DCR) was 80.0%. The Kaplan-Meier estimated median progression-free survival (PFS) was 24 months (95% CI, 9.9-NE). The estimated event-free probability at 12 months was 55% (95% CI, 41.6%-66.5%).

Notably, patients with a baseline LDH above the ULN experienced an ORR of 57.1% with fianlimab plus cemiplimab vs 70.2% for those with normal LDH. The ORR achieved with the doublet in patients without baseline liver metastases was 68.9% vs 47.4% in those with these metastases.

In cohort 6 specifically, patients with LAG-3 expression of at least 1% (n = 27) achieved an ORR of 74.1% vs 40.0% for those with LAG-3 expression below 1% (n = 5); the median PFS in these subsets was 24 months (95% CI, 5.6-NE) and not reached (NR; 95% CI, 1.4-NE), respectively. The ORRs for patients with PD-L1 expression of at least 1% (n = 18) and PD-L1 expression below 1% (n = 16) were 77.8% and 56.3%, respectively; the median PFS in these subsets was 24 months (95% CI, 9.9-NE) and 8.5 months (95% CI, 2.8-NE), respectively.

In those with PD-L1 and LAG-3 expression of at least 1% (n = 18), the ORR was 77.8% vs 66.7% for those with PD-L1 expression below 1% and LAG-3 expression of at least 1% (n = 9); in these subsets, the median PFS was 24 months (95% CI, 9.9-NE) and 5.6 months (95% CI, 1.2-NE), respectively. For patients with PD-L1 and LAG-3 expression below 1% (n = 5), the ORR achieved with the doublet was 40.0%, and the median PFS was NR (95% CI, 1.4-NE).

In cohort 7, patients with prior exposure to anti–PD-1/PD-L1 therapy experienced a median Kaplan-Meier estimated median PFS of 1.5 months (95% CI, 1.3-7.7). The median DOR was NR (95% CI, 3.4-NE), and the DCR was 40.0%. In this cohort, those who had a LAG-3 expression of at least 1% experienced an ORR of 18.2%, as did those with a PD-L1 expression of less than 1%.

Regarding safety, any-grade treatment-emergent AEs (TEAEs) were reported in 96.3% of patients in cohorts 6 and 15 (n = 80); any-grade serious TEAEs occurred in 28.8% of patients. Grade 3 to 5 TEAEs occurred in 40.0% of patients, with grade 3 to 5 serious TEAEs reported in 25.0% of patients. Any-grade treatment-related AEs (TRAEs) occurred in 80% of patients, with serious any-grade TRAEs experienced by 13.8% of patients. Grade 3 or higher TRAEs were observed in 20.0% of patients, with serious grade 3 to 5 TRAEs occurring in 13.8% of patients. Fifteen percent of patients discontinued treatment due to TRAEs, and 2 patients died due to TRAEs; 1 death was due to colitis and 1 death was due to cardiac shock.

Any-grade immune-mediated TEAEs were reported in 65.0% of anti–PD-1/PD-L1–naïve patients, with grade 3 to 5 immune-mediated TEAEs reported in 11.3% of patients. The most common any-grade immune-mediated TEAEs included rash (23.8%), pruritis (15.0%), hypothyroidism (13.8%), arthralgia (12.5%), diarrhea (12.5%), myalgia (10.0%), adrenal insufficiency (8.8%), colitis (7.5%), and pneumonitis (6.3%).

The combination of fianlimab plus cemiplimab is being further investigated vs pembrolizumab or cemiplimab plus placebo in adolescent and adult patients with previously untreated advanced melanoma as part of an ongoing phase 3 trial (NCT05352672).³

References

1. Hamid O, Lewis K, Weise A, et al. Phase 1 study of fianlimab, a human lymphocyte activation gene-3 (LAG-3) monoclonal antibody, in combination with cemiplimab in advanced melanoma. Ann Oncol. 2022;33(suppl 7):S356-S409. doi:10.1016/annonc/annonc1059
2. Hamid O, Wang D, Kim TM, et al. Clinical activity of fianlimab (REGN3767), a human anti-LAG-3 monoclonal antibody, combined with cemiplimab (anti-PD-1) in patients (pts) with advanced melanoma. J Clin Oncol. 2021;39(suppl 15):9515. doi:10.1200/JCO.2021.39.15_suppl.9515
3. Clinical study of fianlimab in combination with cemiplimab in adolescent and adult patients with previously untreated unresectable locally advanced or metastatic melanoma. ClinicalTrials.gov. Updated September 15, 2022. Accessed September 21, 2022. https://clinicaltrials.gov/ct2/show/NCT05352672