In RELATIVITY-047, nivolumab plus relatlimab demonstrated superior progression-free survival (PFS) by blinded independent central review (BICR), with more than a doubling of improvement in median PFS compared with nivolumab alone. Across key prespecified subgroups, PFS favoured nivolumab plus relatlimab. Overall survival (OS) and objective response rate (ORR) remain blinded. In another study, neoadjuvant nivolumab plus relatlimab achieved high rates of pathologic complete response (pCR) and major pathologic response (MPR). Patients with MPR have improved relapse-free survival (RFS) compared to those without MPR with no relapses observed with median 16,2 months follow-up. Nivolumab plus relatlimab is well tolerated with a manageable safety profile and without unexpected safety signals. Both studies were presented at the 2021 ASCO Annual Meeting (4-8 June).

The findings from the RELATIVITY-047 study

Lymphocyte Activation Gene-3 (LAG-3) regulates an immune checkpoint pathway, which inhibits T-cell activity, and is upregulated in many tumour types including melanoma. LAG-3 and PD-1 are distinct and often co-expressed on tumour infiltrating lymphocytes and contribute to tumour-mediated T cell exhaustion.

Relatlimab is a human LAG-3 blocking antibody that restores effector function of exhausted T cells.

In preclinical models, LAG-3 and PD-1 blockade demonstrated synergistic antitumour activity. In addition, relatlimab plus nivolumab demonstrated clinically meaningful antitumour activity including durable objective responses and was well tolerated in patients with melanoma that was relapsed/refractory to anti-PD-1 therapy.

Dr. Evan Jacob Lipson of the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine in Baltimore, MD, US reported that RELATIVITY-047 is a global, randomised, double-blind, phase II/III study evaluating a novel immune checkpoint inhibitor combination of nivolumab plus relatlimab as a fixed-dose combination treatment in first-line advanced melanoma.

Patients with previously untreated advanced melanoma were randomised 1:1 to receive nivolumab plus relatlimab or nivolumab monotherapy. The patients were stratified by LAG-3 expression, PD-L1 expression, BRAF mutation status, and AJCC v8 M stage.

The primary endpoint was PFS per RECIST v1.1 as assessed by BICR. Secondary endpoints were OS and ORR. PFS in prespecified subgroups and safety were additional objectives.

In total, 714 patients were randomised to nivolumab plus relatlimab (n = 355) or nivolumab (n = 359). Patient characteristics were well balanced between treatment groups. Median follow-up was 13.2 months.

Median PFS in the nivolumab plus relatlimab group was 10.1 months (95% confidence interval [CI] 6.4–15.7) and  significantly longer than 4.6 months in the nivolumab group (95% CI 3.4–5.6); hazard ratio 0.75 (95% CI 0.6–0.9; p = 0.0055).

PFS rates at 12 months were 47.7% (95% CI 41.8–53.2) and 36.0% (95% CI 30.5–41.6) for nivolumab plus relatlimab and nivolumab, respectively. PFS favoured nivolumab plus relatlimab across key prespecified subgroups.

The incidence of Grade 3/4 treatment-related adverse events was higher in the nivolumab plus relatlimab group (18.9%) versus nivolumab (9.7%). There were 3 treatment-related deaths with nivolumab plus relatlimab and 2 with nivolumab. Treatment-related adverse events of any grade led to treatment discontinuation in 14.6% and 6.7% of patients in the nivolumab plus relatlimab and nivolumab groups, respectively.

Dr. Lipson concluded that this is the first phase III study to validate dual inhibition of the LAG-3 and PD-1 pathways. Nivolumab plus relatlimab demonstrated a statistically significant PFS benefit compared to nivolumab monotherapy and it is a potential new treatment option for patients with advanced melanoma, bringing the benefits of dual checkpoint inhibition to more patients.

Dr. Jason J Luke of the UPMC Hillman Cancer Center, University of Pittsburgh in Pittsburgh, PA, US who discussed the study data said that statistically significant and clinically meaningful improvement in PFS was observed with nivolumab plus relatlimab. Toxicity was manageable above anti-PD1 monotherapy.

This combination represents a new standard of care that should replace anti-PD1 antibody alone. However, he would not treat with this combination rapid progressors/high LDH, brain, liver and bone metastases, bulky disease where he would prefer ipilimumab plus nivolumab, patients progressing on adjuvant PD-1 antibody where he would prefer ipilimumab plus nivolumab, and patients with severe autoimmune disease where he would prefer nivolumab or pembrolizumab monotherapy.

He questioned where to go next in the research agenda, with a combination of nivolumab plus relatlimab plus low-dose ipilimumab and moving to adjuvant studies (stage II) and neoadjuvant setting.

The study was sponsored by Bristol-Myers Squibb.

Neoadjuvant and adjuvant nivolumab plus relatlimab for resectable clinical stage III melanoma

Neoadjuvant therapy for patients with clinical stage III melanoma is an active area of research interest. More robust immune responses are seen with neoadjuvant immunotherapy compared to adjuvant due to an intact tumour microenvironment. Advantages of neoadjuvant approach are ability to identify patients with the pCR which can serve as a surrogate marker for improved clinical outcomes, ability to tailor adjuvant therapy depending on neoadjuvant response, ability to collect longitudinal biospecimens to understand mechanisms of treatment response and resistance, earlier onset of systemic therapy to potentially eradicate micrometastases, and shrinkage of disease preoperatively may decrease surgical morbidity.

Dr. Rodabe Navroze Amaria of The University of Texas MD Anderson Cancer Center in Houston, TX, US and colleagues hypothesized that neoadjuvant therapy with nivolumab plus relatlimab will safely achieve high pCR rates and provide insights into mechanisms of response and resistance to this regimen.

The study team conducted a multi-institutional, investigator-initiated single arm study that enrolled patients with clinical stage III or oligometastatic stage IV melanoma with RECIST v1.1 measurable, surgically-resectable disease. Patients were enrolled at 2 sites and received nivolumab plus relatlimab. Radiographic response according RECIST v1.1 was assessed after completion of neoadjuvant therapy. Surgery was conducted at week 9 and specimens were assessed for pathologic response per established criteria. Patients received up to 10 additional doses of nivolumab plus relatlimab after surgery, with scans every 3 months to assess for recurrence.

The primary study objective was determination of pCR rate. Secondary objectives included safety, radiographic response by RECIST v1.1, event-free survival (EFS), RFS, and OS analyses. Blood and tissue were collected at baseline, at day 15, day 28, and at surgery for correlative analyses.

A total of 30 patients of whom 19 were males, with median age of 60 years, were enrolled: 18 with clinical stage IIIB, 8 with stage IIIC, 2 with stage IIID, and 2 with stage IV (M1a). In total 29 patients underwent surgery; 1 patient developed distant metastatic disease while on neoadjuvant therapy.

The pCR rate was 59% and near pCR defined as <10% viable tumour was 7% for MPR (pCR plus near pCR) of 66%; 7% of patients achieved a pPR defined as 10-50% viable tumour and 27% pNR defined as ≥50% viable tumour.

Overall radiographic response rate was 57%. With a median follow up of 16.2 months, the 1-year EFS was 90%, RFS was 93%, and OS was 95%; the 1-year RFS for MPR was 100% compared to 80% for non-MPR pts (p = 0.016).

Nivolumab plus relatlimab was well tolerated; there were no treatment related Grade 3/4 adverse events that arose during neoadjuvant therapy and 26% of patients had a Grade 3/4 adverse events in the adjuvant setting.

Translational studies demonstrate increased effector CD8 T cell population and decreased immunosuppressive M2 macrophages in tumours of MPR patients.

The authors concluded that compared to other neoadjuvant regimens, nivolumab plus relatlimab produces similar efficacy, but reduced toxicity.

Prof. Alexander Menzies of the Melanoma Institute Australia, The University of Sydney, Royal North Shore and Mater Hospitals who discussed the study data said that neoadjuvant therapy is a future, as providing robust model for drug development.

The study was sponsored by Bristol Myers Squibb and MD Anderson Melanoma Moonshot Program.