Relatlimab Plus Nivolumab/Chemo Misses ORR End Point in LAG-3+ Advanced Gastric/GEJ Cancer

Treatment with the combination of relatlimab and nivolumab (Opdualag) plus chemotherapy did not improve overall response rate (ORR) vs nivolumab (Opdivo) plus chemotherapy in patients with previously untreated advanced gastric or gastroesophageal junction (GEJ) cancer harboring a LAG-3 expression of at least 1%, missing the primary end point of the phase 2 RELATIVITY-060 trial (NCT03662659).¹

Findings published in the Journal of Clinical Oncology showed that patients with a LAG-3 expression of at least 1% treated with relatlimab plus nivolumab and chemotherapy (n = 97) achieved an ORR of 48% (95% CI, 38%-59%) compared with 61% (95% CI, 51%-71%) for patients treated with nivolumab plus chemotherapy (n = 98) per blinded independent central review (BICR) assessment (difference, –13%; 70% CI, –20% to –6%; P = .0711).

In the triplet arm, the complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) rates were 6%, 42%, 35%, and 1%, respectively. Those respective rates in the doublet arm were 10%, 51%, 18%, and 10%. Notably, response was unable to be determined in 7% of patients in the relatlimab arm and 5% of patients in the control arm. The disease control rate (DCR) was 92% (95% CI, 84%-96%) in the relatlimab arm vs 85% (95% CI, 76%-91%) in the nivolumab/chemotherapy arm.

In patients with a LAG-3 expression of less than 1%, the triplet (n = 41) elicited a BICR-assessed ORR of 32% (95% CI, 18%-48%) vs 55% (95% CI, 38%-71%) for the doublet (n = 38; difference, –25%; 70% CI, –36% to –15%). Patients treated with relatlimab plus nivolumab and chemotherapy experienced a CR rate of 5%, a PR rate of 27%, an SD rate of 27%, and a PD rate of 5%. Those respective rates were 0%, 55%, 18%, and 11% for patients treated with nivolumab plus chemotherapy. The DCRs for the experimental and control arms were 78% (95% CI, 62%-89%) and 89% (95% CI, 75%-97%), respectively.

“Adding relatlimab to nivolumab plus chemotherapy, the current standard of care, did not show improved response in patients with gastric/GEJ cancer; however, a trend toward improved progression-free survival [PFS] in the small subgroup of patients with LAG-3 expression of at least 5% was observed and may warrant further investigation,” lead study author Susanna Hegewisch-Becker, MD, PhD, of Hematology-Oncology Practice Eppendorf in Hamburg, Germany, and colleagues, wrote in a publication of the data.

The randomized, open-label, multicenter RELATIVITY-060 trial enrolled patients at least 18 years of age with histologically or cytologically confirmed, unresectable, locally advanced or metastatic gastric or GEJ adenocarcinoma who had not received prior systemic therapy. Notably, prior neoadjuvant or adjuvant chemotherapy, radiotherapy, or chemoradiotherapy were allowed if treatment was given at least 6 months prior to enrollment.

Other key inclusion criteria included an ECOG performance status of 0 or 1; at least 1 measurable lesion per RECIST 1.1 criteria; and tumor tissue for biomarker analysis.

Patients were excluded if they had HER2-positive disease; had known, untreated central nervous system metastases; or had uncontrolled or significant cardiovascular disease.²

RELATIVITY-060 was conducted at 70 centers across 17 countries in Asia, Europe, North America, South America, and Australia. Patients were randomly assigned 1:1 to receive relatlimab plus nivolumab and chemotherapy or nivolumab plus chemotherapy. Investigator’s choice of chemotherapy regimens consisted of oxaliplatin plus capecitabine (XELOX); oxaliplatin plus leucovorin and fluorouracil (FOLFOX); or oxaliplatin plus tegafur/gimeracil/oteracil potassium (SOX).¹

Patients assigned to receive XELOX were given relatlimab at 120 mg plus nivolumab 360 mg, or nivolumab at 360 mg alone on days 1 and 22 of each 6-week cycle. Oxaliplatin was administered at 130 mg/m² on days 1 and 22 of each cycle, and capecitabine was given at 1,000 mg/m² twice per day on days 1 to 14 and 22 to 35 of each cycle.

For patients assigned to FOLFOX, 160 mg of relatlimab plus 480 mg of nivolumab, or 480 mg of nivolumab alone, were administered on days 1 and 29 of every odd-numbered 6-week cycle. FOLFOX was given as 85 mg/m2 of oxaliplatin, 400 mg/m² of leucovorin, and 400 mg/m² of fluorouracil on days 1, 15, and 29 of each cycle. Fluorouracil was also given at 1,200 mg/m² on days 1, 2, 15, 16, 29, and 30 of each cycle.

“Dose escalations or reductions of nivolumab plus relatlimab or nivolumab were not allowed. Dose modifications, delays, and discontinuation of chemotherapy components could be modified separately and were permitted according to local standards,” study authors wrote.

Stratification factors included LAG-3 expression (≥1% vs <1%) and PD-L1 combined positive score (CPS; <1 vs ≥1 to <5 vs ≥5).

Along with the primary end point of ORR per BICR assessment in the population of patients with a LAG-3 expression of at least 1%, secondary end points included safety; BICR-assessed ORR in patients with a LAG-3 expression of less than 1% and all randomly assigned patients; investigator-assessed ORR; duration of response (DOR); PFS; and overall survival (OS).

Among all enrolled patients in the relatlimab arm (n = 138) and the control arm (n = 136), the median age was 62 years (range, 24-79) and 63 years (range, 23-84), respectively. The majority of patients in both arms were male (experimental, 68%; control, 72%), were White (93%; 90%), were from Europe (51%; 57%), had an ECOG performance status of 1 (60%; 54%), and had metastatic disease (93%; 90%). In the relatlimab arm, 49% of patients had gastric cancer, and 51% of patients had GEJ cancer. Those rates were 51% and 49%, respectively, in the nivolumab plus chemotherapy arm.

Additionally, 46% of patients in the relatlimab arm had baseline liver metastases, and 41% had baseline peritoneal metastases. Those respective rates were 38% and 43% in the control arm. PD-L1 CPS in the experimental arm consisted of less than 1 or indeterminate (21%); at least 1 and less than 5 (25%); and at least 5 (54%). In the control arm, those respective PD-L1 CPS rates were 24%, 21%, and 55%.

Seventy-five percent of patients in the relatlimab arm received FOLFOX, and 25% were given XELOX. Those respective rates were 71% and 28% for the control arm. Prior treatment included adjuvant therapy (experimental arm, 3%; control arm, 8%), neoadjuvant therapy (13%; 15%), locally advanced therapy (<1% each), radiotherapy (15%; 17%), and surgery (33%; 35%).

Additional data showed the investigator-assessed ORR in patients with a LAG-3 expression of at least 1% was 53% (95% CI, 42%-63%) for relatlimab plus nivolumab and chemotherapy vs 56% (95% CI, 46%-66%) for nivolumab plus chemotherapy. In patients with a LAG-3 expression of less than 1%, the respective investigator-assessed ORRs were 32% (95% CI, 18%-48%) and 42% (95% CI, 26%-59%).

In the population of patients with a LAG-3 expression of at least 1%, the BICR-assessed median time to response (TTR) was 1.5 months (range, 1.2-5.3) for the relatlimab regimen vs 1.5 months (range, 1.2-5.6) for nivolumab plus chemotherapy. The respective DORs were 5.7 months (95% CI, 4.4-10.0) and 10.1 months (95% CI, 6.4-13.3). The median PFS was 7.0 months (95% CI, 5.8-8.4) in the experimental arm vs 8.3 months (95% CI, 6.9-12.1) in the control arm (HR, 1.41; 95% CI, 0.97-2.05). The median OS was 13.5 months (95% CI, 11.9-19.1) vs 16.0 months (95% CI, 10.9–not evaluable), respectively (HR, 1.04; 95% CI, 0.70-1.54).

For patients with a LAG-3 expression of less than 1%, those treated with relatlimab plus nivolumab and chemotherapy experienced a BICR-assessed median TTR of 1.6 months (range, 1.3-4.0) and a median DOR of 5.4 months (95% CI, 3.3-7.0). Patients in the nivolumab plus chemotherapy arm had a median TTR of 2.8 months (range, 1.2-7.2) and a median DOR of 8.5 months (95% CI, 5.3-13.6). The median PFS was 6.6 months (95% CI, 4.7-7.1) in the experimental arm vs 9.7 months (95% CI, 6.9-13.7) in the control arm (HR, 2.15; 95% CI, 1.23-3.76). The median OS was 9.7 months (95% CI, 6.6-12.8) and 16.8 months (95% CI, 11.4-17.6), respectively (HR, 2.16; 95% CI, 1.23-3.82).

An exploratory analysis showed that in patients with LAG-3 expression of least 5% (n = 37), those treated with relatlimab plus nivolumab and chemotherapy achieved a median PFS of 13.1 months compared with 6.9 months for those given nivolumab plus chemotherapy (unstratified HR, 0.75; 95% CI, 0.32-1.77), and the median OS was not reached in both arms.

Regarding safety, any-grade treatment-related adverse effects (TRAEs) occurred in 91% of patients treated in the relatlimab arm vs 96% of patients in the control arm. The rates of grade 3/4 TRAEs were 69% for the relatlimab arm compared with 61% for the nivolumab plus chemotherapy alone arm. One grade 5 TRAE was reported in the nivolumab plus chemotherapy arm. The rates of serious any-grade TRAEs were 38% in the relatlimab plus nivolumab and chemotherapy arm vs 28% in the nivolumab plus chemotherapy arm. Any-grade TRAEs leading to treatment discontinuation occurred in 42% of patients in the experimental arm vs 36% of patients in the control arm.

The most common grade 3/4 TRAEs included neutropenia (experimental arm, 21%; control arm, 17%), fatigue (7%; 7%), diarrhea (4%; 6%), and peripheral neuropathy (4%; 7%).

“Additional studies may identify subgroups of patients that could benefit from relatlimab-based therapies to treat unresectable, locally advanced or metastatic gastric/GEJ cancer,” study authors concluded.

References

1. Hegewisch-Becker S, Mendez G, Chao J, et al. First-line nivolumab and relatlimab plus chemotherapy for gastric or gastroesophageal junction adenocarcinoma: the phase II RELATIVITY-060 study. J Clin Oncol. Published online May 9, 2024. doi:10.1200/JCO.23.01636
2. An investigational study of immunotherapy combinations with chemotherapy in patients with gastric or gastroesophageal junction (GEJ) cancers. ClinicalTrials.gov. Updated February 13, 2024. Accessed May 14, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT03662659