Relatlimab / Nivolumab application for advanced first-line melanoma validated by the EMA

The European Medicines Agency has validated its marketing authorization request for the fixed-dose combination of relatlimab and nivolumab (Opdivo) in the first-line treatment of adult and pediatric patients with advanced melanoma.¹

The filing follows the first results of the phase 2/3 trial RELATIVITY-047 (NCT03470922), which showed that the doublet resulted in a median progression-free survival (PFS) of 10.12 months (95% CI, 6.37-15.74) vs 4.63 months (95% CI, 3 , 38-5.62) with nivolumab monotherapy (hazard ratio [HR], 0.75; 95% CI: 0.62-0.92; P = 0.0055); this resulted in an improvement of 5.49 months.

In addition, the 12-month PFS rate in the investigation arm was 47.7% (95% CI, 41.8% to 53.2%) versus 36.0% (95% CI, 30 , 5 to 41.6%) in the control arm. Notably, the benefit of PFS demonstrated with the fixed dose regimen was observed regardless of the predefined subgroups and stratification factors.

“Melanoma can be a devastating disease and cases have been on the rise for years. RELATIVITY-047 trial results demonstrate the potential of the fixed-dose combination relatlimab and nivolumab for people with advanced forms of this cancer, ”said Jonathan Cheng, senior vice president and head of oncology development at Bristol Myers Squibb, in a statement. Press release. “If approved, this treatment would become the first of its kind available to patients in the European Union. We look forward to working with the EMA to evaluate this combination – which includes our separate third checkpoint inhibitor – and are proud of this first step towards making it available to patients with advanced melanoma.

The global, double-blind, phase 2/3 RELATIVITY-047 trial enrolled 714 treatment-naïve patients with unresectable or metastatic melanoma who had an ECOG performance index of 0 or 1.) relatlimab 160 mg plus nivolumab 480 mg every 4 weeks or nivolumab IV alone, given at 480 mg every 4 weeks.

Patients were stratified according to LAG-3 and PD-L1 status, BRAF American Joint Committee on Cancer (AJCC) version 8 mutation status and metastatic stage.

The primary endpoint of the research was blinded independent central examination (BICR) PFS. Secondary endpoints included overall survival (OS) and overall response rate (ORR) by BICR.

The median age of participants in the treatment arms was 63 years and 41.7% were female. In addition, 66.9% of patients had an ECOG performance index of 0 and 36.1% had a serum lactate dehydrogenase level above the upper limit of normal; 38.9% of patients had an AJCC v.8 metastatic stage of M1C and 2.4% had a stage of M1D.

Just over 8% of patients (8.4%) received previous neoadjuvant or adjuvant therapy. In the combined arm, the median tumor burden was 59.0 mm versus 54.5 mm in the monotherapy arm. In addition, 75.2% of patients had LAG-3 expression of 1% or greater, 59.0% had PD-L1 expression less than 1%, 61.5% had BRAF wild type disease and 65.7% had an AJCC metastatic stage of M0 / M1any (0).

RELATIVITY-047 Supplementary Data presented at the ASCO Annual Meeting 2021 revealed that the RR for PFS in the acral cutaneous melanoma subset of patients was 0.84 (95% CI, 0.50-1.39); in people with non-acral skin disease, mucosal disease, and other subtypes, the RRs for PFS were 0.73 (95% CI, 0.57-0.93) , 0.72 (95% CI, 0.36-1.45) and 0.77 (95% CI, 0.44-1.36), respectively.²

The benefit of PFS has been shown to favor the fixed dose doublet over monotherapy, regardless of LAG-3 expression status. Among those with 1% or greater LAG-3 expression who were randomized to the investigation (n = 268) or control (n = 269) arms, the median PFS was 12.58 months (CI at 95%, 6.67-23.10) and 4.76 months (95% CI, 4.47-8.61), respectively (RR, 0.75; 95% CI, 0.59-0 , 95). In those with less than 1% expression, the median PFS with the doublet (n = 87) was 4.83 months (95% CI, 2.86-10.05) versus 2.79 months (CI 95%, 2.79-4.63) with monotherapy (n = 90; RR: 0.78; 95% CI: 0.54-1.15).

Additional findings shared during the ESMO Congress 2021 demonstrated that those who received the fixed dose combination and stopped treatment (n = 167) experienced a longer treatment-free interval (TFI) than those who received nivolumab as monotherapy (n = 151).³ The median TFI in the investigation and control arms was 3.32 months (range, 0.1-30.4) and 1.41 months (range, 0.1-25.6), respectively.

Relatlimab / nivolumab also resulted in a reduced risk of progression after next-line systemic therapy (PFS2), as assessed by the investigator, or death compared to nivolumab as monotherapy. The median PFS2 had not yet been reached (95% CI, 21.75 – not reached) with the doublet vs 20.04 months (95% CI, 15.44-25.13) with the monotherapy (RR : 0.77; 95% CI: 0.61 to 0.97).

The median duration of treatment in the investigation and control arms was 5.6 months and 4.9 months, respectively, and 66.8% and 64.9% of patients, respectively, discontinued treatment. The most common reasons for discontinuing treatment included disease progression (36.3% vs. 46.0%, respectively), treatment-related adverse reactions (AEs; 17.7% vs. 8.9%), patient demand (5.4% vs. 3.3%) and toxicity that was not associated with treatment (3.4% vs. 3.9%).

In addition, 37.3% of patients who received nivolumab received only subsequent treatment compared to 35.5% of those who received the doublet; 29.8% and 27.9% of patients, respectively, received systemic therapy.

In the investigation and control arms, subsequent treatments included inhibitors of PD-1 and / or CTLA-4 (9.0% vs. 12.8%, respectively), inhibitors of BRAF and / or MEK ( 11.5% vs. 13.9%) or other systemic options (10.7% vs. 12.3%). In addition, 11.5% of people on relatlimab / nivolumab versus 10.0% of those on nivolumab as monotherapy received radiotherapy; 5.1% vs. 2.7%, respectively, had surgery.

In addition, 40.7% of non-treatment patients included in the TFI analysis who received the doublet did not receive subsequent systemic therapy, compared with 29.1% of those who received nivolumab as monotherapy. In the doublet and monotherapy arms, 31.1% and 37.7% of patients, respectively, received subsequent treatment.

Regarding safety, the doublet was found to be tolerable and presented no new signals.

Monitoring of OS and ORR secondary endpoints is ongoing.

Earlier in September 2021, the FDA granted priority review to biologics license application for relatlimab plus nivolumabfor use in adult and pediatric patients 12 years of age and over who weigh 40 kg or more and who have unresectable or metastatic melanoma. The app is based on data from RELATIVITY-047.⁴

The references

1. The European Medicines Agency validates Bristol Myers Squibb’s request for the fixed-dose combination of LAG-3 blocking antibodies relatlimab and nivolumab as first-line treatment for patients with unresectable or metastatic melanoma. Press release. Bristol Myers Squibb. October 1, 2021. Accessed October 1, 2021. https://bit.ly/3l1KJja
2. Lipson EJ, Tawbi HA, Schadendorf D, et al. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in advanced first-line melanoma: primary phase III results of RELATIVITY-046 (CA224-047). J Clin Oncol. 2021; 39 (suppl 15): 9503. doi: 10.1200 / JCO.2021.39.15_suppl.9503
3. Hodi FS, Tawbi HA, Lipson EJ et al. Relatlimab (RELA) + nivolumab (NIVO) versus NIVO in untreated metastatic or unresectable melanoma: additional efficacy in RELATIVITY-047. Presented at: ESMO 2021 Congress; September 16-21, 2021; Virtual. Abstract 1036O.
4. U.S. Food and Drug Administration Accepts Bristol Myers Squibb’s Request for Priority Review for Fixed-Dose Combination of LAG-3 Blocking Antibodies, Relatlimab, and Nivolumab, as Treatment for Patients with Unresectable Melanoma or metastatic. Press release. Bristol Myers Squibb. September 20, 2021. Accessed October 1, 2021. https://bit.ly/3tVGyYG