Nivolumab plus relatlimab and nivolumab plus ipilimumab for patients with advanced renal cell carcinoma: results from the open-label, randomised, phase II FRACTION-RCC trial

Abstract

Background

The Fast Real-time Assessment of Combination Therapies in Immuno-ONcology study in patients with aRCC (FRACTION-RCC) was designed to assess new immuno-oncology (IO) combinations in patients with advanced renal cell carcinoma (aRCC). We present results in IO-naive patients treated with nivolumab (NIVO) + relatlimab (RELA) or NIVO + ipilimumab (IPI) in track 1.

Methods

The open-label, randomised, phase II FRACTION-RCC trial enrolled patients with aRCC from 32 hospitals and cancer centres across six countries. Patients were enrolled in track 1 (IO-naive) or track 2 (IO-experienced). IO-naive patients were stratified by previous tyrosine kinase inhibitor therapy and randomised to NIVO (240 mg) + RELA (80 mg) intravenously once every 2 weeks or NIVO (3 mg/kg) + IPI (1 mg/kg) intravenously once every 3 weeks for four doses, followed by NIVO (480 mg) once every 4 weeks, each up to ∼2 years. The primary endpoints were objective response by investigator (RECIST version 1.1), duration of response (DOR), and progression-free survival (PFS) rate at 24 weeks. Safety was a secondary endpoint; biomarker analyses were exploratory.

Results

FRACTION-RCC enrolled patients between 2 February 2017 and 23 January 2020. In track 1, 30 patients each were treated with NIVO + RELA or NIVO + IPI (clinical database lock, 1 November 2021). With NIVO + RELA [median follow-up, 48.6 months; interquartile range (IQR) 46.9-51.7 months], objective response was 30% [95% confidence interval (CI) 15% to 49%], with 33 weeks (95% CI 16-53 weeks) median DOR. The PFS rate at 24 weeks was 43% (95% CI 25% to 60%). With NIVO + IPI (median follow-up, 48.7 months; IQR 47.1-52.0 months), the objective response was 20% (95% CI 8% to 39%), with the median DOR not reached (95% CI 33 weeks-not estimable). The PFS rate at 24 weeks was 49% (95% CI 29% to 66%). Higher baseline lymphocyte activation gene 3 (LAG-3) and programmed death-ligand 1 (PD-L1) expression levels were detected among track 1 NIVO + RELA responders. Grade 3-4 treatment-related adverse events were reported in 4/30 (13%) patients treated with NIVO + RELA and 10/30 (33%) patients treated with NIVO + IPI. No deaths were attributed to study treatments.

Conclusions

Results showed antitumour activity and manageable safety with NIVO + RELA. Findings also support NIVO + IPI as an effective combination regimen in IO-naive patients with aRCC.

Highlights

• •We report dual checkpoint inhibition with NIVO (anti-PD-1) + RELA (anti-LAG-3) or IPI (anti-CTLA-4) in IO-naïve aRCC pts.
• •With 48.6 mo median follow-up in the NIVO+RELA arm, ORR was 30% and median DOR was 33 wk, with a 43% PFS rate at 24 wk.
• •With 48.7 mo median follow-up in the NIVO+IPI arm, ORR was 20% and median DOR was not reached, with a 49% PFS rate at 24 wk.
• •Antitumour effects were observed in subgroups by LAG-3 and PD-L1 expression.
• •The safety profiles for NIVO + RELA and NIVO + IPI were consistent with previous reports for each combination.

Introduction

The prognosis for patients with advanced renal cell carcinoma (aRCC) has improved significantly over the past decade with the advent of immuno-oncology (IO)-based therapies.1, 2, 3, 4 Initial clinical data demonstrated significant antitumour activity with the single-agent immunotherapy nivolumab (NIVO). NIVO is an anti-programmed cell death protein 1 (PD-1) monoclonal antibody that selectively blocks the PD-1–programmed death-ligand 1 (PD-L1) axis, leading to restored antitumour immunity.^1,5 More recently, checkpoint inhibitor-based combination therapies have demonstrated increased overall survival (OS) and a greater depth and duration of response (DOR) versus sunitinib in patients with aRCC [NIVO + ipilimumab (IPI), pembrolizumab + axitinib, NIVO + cabozantinib, and lenvatinib + pembrolizumab].^3,6, 7, 8 The combination of NIVO + IPI was the first and only dual checkpoint inhibitor-based combination therapy to demonstrate superior efficacy versus sunitinib in aRCC.⁹ NIVO + IPI was subsequently approved in 2018 by the United States Food and Drug Administration (FDA) and in 2019 by the European Commission for the first-line treatment of patients with International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate-risk and poor-risk aRCC.^9,10 NIVO + IPI has continued to demonstrate significant long-term OS and response benefits over sunitinib at a minimum follow-up of 5 years.³

Following the success of anti-PD-1 and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathway-targeted agents, recent studies have identified other novel immune checkpoint targets, including lymphocyte activation gene 3 (LAG-3).¹¹ LAG-3 is another immune checkpoint that can be coexpressed with PD-1, and is being evaluated as a potential mechanism of resistance to immune checkpoint inhibition.^12,13 LAG-3 is a cell-surface molecule expressed on T cells and other immune cells with inhibitory effects on the function of T cells.¹⁴ Preclinical data suggest that simultaneous activation of the LAG-3 and PD-1 pathways in tumour-infiltrating lymphocytes results in greater T-cell dysfunction than either signalling pathway alone.15, 16, 17

NIVO + relatlimab (RELA) combination therapy enables T-cell activation and proliferation, leading to the initiation of an improved immune response and promoting tumour cell death.^15,18 Dual inhibition of the LAG-3 and PD-1 checkpoints via the combination of RELA with NIVO restores T-cell activity, leading to an improved antitumour immune response greater than the effects of either antibody alone.^14,19 In 2022, RELA in combination with NIVO was approved in the United States for the first- and second-line treatment of patients with unresectable or metastatic melanoma, and in Europe for patients with untreated advanced melanoma with tumour PD-L1 expression of <1%.^14,20

The Fast Real-time Assessment of Combination Therapies in Immuno-ONcology study in patients with aRCC (FRACTION-RCC) is a signal-seeking, randomised phase II study with an adaptive platform design that enables rapid evaluation of different IO treatment combinations. FRACTION-RCC was designed to integrate new combination regimens as they become available and withdraw ineffective regimens, with the goal of reducing the time and number of patients required to identify potentially beneficial therapies for further evaluation in larger phase II or III trials.²¹ Patients were enrolled in one of two tracks. In track 1, eligible patients were anti-PD-1, anti-PD-L1, and anti-CTLA-4 treatment naive. In track 2, eligible patients had received previous anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment; NIVO + IPI results from track 2 have been reported.²² Here, we focus on assessments of IO-naive patients treated with NIVO + RELA or NIVO + IPI in track 1. Treatment groups were assessed individually, as the study was not designed to make direct comparisons between arms.

Methods

Study design and patients

FRACTION-RCC is an open-label, randomised, multicentre phase II trial conducted in 32 hospitals and cancer centres across six countries on four continents. The master FRACTION study design was described previously and applied to all combination treatments selected for evaluation.²¹ Briefly, in FRACTION-RCC, patients were enrolled in one of two tracks (Supplementary Figures S1 and S2, available at https://doi.org/10.1016/j.esmoop.2024.104073).²² Track 1 enrolled patients with aRCC who were naive to IO treatment (anti-PD-1/anti-PD-L1 and anti-CTLA-4) and were stratified according to previous tyrosine kinase inhibitor (TKI) treatment. Track 2 enrolled patients with previous IO treatment (anti-PD-1/anti-PD-L1 and anti-CTLA-4). We focus here on outcomes in IO-naive (track 1) patients randomised to receive NIVO + RELA or NIVO + IPI.

Eligibility criteria were published previously.²² Briefly, adults (aged ≥18 years) with histologically confirmed clear cell advanced or metastatic (stage IV) RCC and one or more lesion with measurable disease per RECIST version 1.1 were included. Patients previously treated with TKIs, adjuvant or neoadjuvant treatment with interleukin 2, interferon alpha, or radiotherapy ≥4 weeks before randomisation were eligible. Full eligibility criteria are listed in the protocol (Supplementary Appendix, available at https://doi.org/10.1016/j.esmoop.2024.104073). Study participants self-reported sex at birth (options: male or female).

Safety and eligibility were monitored at the discretion of the medical monitor and investigator. FRACTION-RCC was approved by an institutional review board or independent ethics committee and regulatory authorities at the participating institutions and conducted in accordance with Good Clinical Practice guidelines as defined by the International Council on Harmonisation in accordance with the ethical principles underlying European Union Directive 2001/20/EC and the United States Code of Federal Regulations, Title 21, Part 50 (21CFR50). All patients provided written informed consent according to the principles of the Declaration of Helsinki. Between 23 August 2016 and 11 January 2022, seven protocol amendments were made which included changes that affected study design and recruitment. Full details of the revisions are available in the protocol (Supplementary Appendix, available at https://doi.org/10.1016/j.esmoop.2024.104073).

Randomisation and masking

Patients were randomly assigned (1 : 1) to receive NIVO + RELA or NIVO + IPI via an interactive response system (Supplementary Figure S2, available at https://doi.org/10.1016/j.esmoop.2024.104073). The allocation sequence was generated by the Bristol Myers Squibb (Princeton, NJ) interactive response technology team.

Patients enrolled in track 1 or 2 were randomised to receive NIVO + RELA, NIVO + IPI, or other treatment combinations, all of which included NIVO (Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2024.104073). Patients with disease progression after treatment in track 1 or 2 were eligible to enrol from track 1 into track 2, or to re-enrol in track 2 to be randomised to receive a new IO treatment combination. Patients and investigators were not masked to study treatment in this open-label trial.

Procedures

Patients in the NIVO + RELA group received NIVO (240 mg) + RELA (80 mg) intravenously every 2 weeks. In the NIVO + IPI group, patients received NIVO (3 mg/kg) + IPI (1 mg/kg) intravenously every 3 weeks for four doses, followed by NIVO (480 mg) monotherapy every 4 weeks. Each regimen continued for up to ∼2 years of treatment or until disease progression, toxicity, clinical deterioration, or protocol-specified discontinuation. Doses of study treatment could be interrupted, delayed, or discontinued depending on tolerability, but dosing visits could not be skipped.

Tumour assessments were carried out by computed tomography or magnetic resonance imaging of the abdomen, chest, pelvis, and all known sites of disease. These assessments were completed at baseline (≤28 days before the first dose of study treatment) and every 8 weeks (including week 24) during the treatment phase or until investigator-assessed disease progression per RECIST version 1.1, confirmation of disease progression for patients treated beyond progression, discontinuation of study treatment, or withdrawal from the study.

Outcomes

Final analyses for the primary efficacy endpoints were carried out on the all-treated population, defined as all randomised patients who received at least one dose of study treatment. The primary endpoints were objective response, median DOR, and progression-free survival (PFS) rate at 24 weeks per investigator using RECIST version 1.1. The secondary outcomes were safety and tolerability. The secondary endpoint of safety assessed the incidence of adverse events (AEs), serious AEs, AEs leading to discontinuation, and deaths. Immune-mediated AEs were also assessed. All AEs were graded using the NCI Common Terminology Criteria for Adverse Events version 4.03. OS and select biomarker assessments were exploratory outcomes. Exploratory biomarker analyses included study results by LAG-3 and PD-L1 expression and were reported separately from the main clinical study report. Biomarker data were based on the immunohistochemistry-assessable cohort of all treated patients, defined as the set of patients with assessable results for PD-L1 (PD-L1 analyses) or both PD-L1 and LAG-3 expression (LAG-3 analyses). PD-L1 expression was defined as the percentage of tumour cells with membrane staining in ≥100 evaluable tumour cells using the Dako PD-L1 IHC 28-8 pharmDx assay (Agilent, Santa Clara, CA). LAG-3 expression was defined as the percentage of LAG-3-positive lymphocytes in all cells, estimated for the entire tumour region and peritumoural stroma using 17B4 antibody.

Statistical analysis

Sample sizes were guided by Simon’s two-stage (optimal) designs. Recommendations for stopping or progressing to the next stage were based on the number of objective responses observed. A false-positive rate of 5% and power of 90% were used. In track 1, ≥24 patients per arm were to be treated in stage 1 for an initial evaluation of efficacy. On the observation of eight or fewer responses of 24 patients, the study treatment arm was not considered efficacious. However, on the observation of more than eight responses, stage 2 was initiated, and an additional 39 patients were to be treated. If there were ≤24 total responses of 63 patients at the end of stage 2, the study treatment arm was ended for futility; if >24 responses were observed at the end of stage 2, the study treatment progressed toward further development. The totality of efficacy data and response profile for each combination were considered when deciding to terminate or continue a treatment group. FRACTION-RCC enrolment ended early due to the changing treatment landscape and approvals of additional treatment options for patients with aRCC.

Protein biomarker expression was summarised using descriptive statistics. P values were not reported due to the relatively low number of patients available for the biomarker analyses.

Safety data were monitored by an independent safety monitoring board. All statistical analyses were carried out with SAS (version ≥9.2; SAS Institute, Cary, NC). This study is registered with https://clinicaltrials.gov/study/NCT02996110 ClinicalTrials.gov (NCT02996110).

Results

In total, 248 patients with aRCC were enrolled in the FRACTION-RCC trial between 2 February 2017 and 23 January 2020 (Supplementary Figures S1 and S2, available at https://doi.org/10.1016/j.esmoop.2024.104073). We focused on the 60 IO-naive patients treated with NIVO + RELA (n = 30) or NIVO + IPI (n = 30) in track 1 of this study and included them in the efficacy and safety analyses. IO-experienced patients treated with NIVO + RELA in track 2 (n = 32) are included in the Supplementary Appendix, available at https://doi.org/10.1016/j.esmoop.2024.104073, for completeness; results for NIVO + IPI in track 2 have been reported.²²

Baseline demographic and clinical characteristics are shown in Table 1. In the NIVO + RELA group, the median age was 55 years [interquartile range (IQR) 46-65 years], most patients were white (90%), male (70%), and had IMDC intermediate risk [73%; favourable risk (10%); poor risk (17%)]. In the NIVO + IPI group, the median age was 60 years (IQR 55-66 years), 100% of patients were white, and most were male (73%), while patients were split between favourable (43%), intermediate (37%), or poor (17%) risk. Ninety percent of patients had stage IV disease at study entry in either group.

Table 1.

Baseline demographic and clinical characteristics in IO-naive patients treated with NIVO + RELA or NIVO + IPI in track 1

	NIVO + RELA group (n = 30)	NIVO + IPI group (n = 30)
Age, median (range), years	55 (36-79)	60 (41-79)
<65, n (%)	22 (73.3)	21 (70.0)
≥65, n (%)	8 (26.7)	9 (30.0)
Sex (male), n (%)	21 (70.0)	22 (73.3)
Race, n (%)
White	27 (90.0)	30 (100)
Asian	1 (3.3)	0 (0)
Other	2 (6.7)	0 (0)
IMDC risk groupa, n (%)
Favourable	3 (10.0)	13 (43.3)
Intermediate	22 (73.3)	11 (36.7)
Poor	5 (16.7)	5 (16.7)
Not reported	0 (0)	1 (3.3)
Stage of disease at study entry, n (%)
III	3 (10.0)	3 (10.0)
IV	27 (90.0)	27 (90.0)
Previous systemic therapy, n (%)	23 (76.7)	23 (76.7)
Chemotherapy	0 (0)	0 (0)
Targeted therapy	16 (53.3)	18 (60.0)
TKI	16 (53.3)	18 (60.0)
Immunotherapy, n (%)	11 (36.7)	10 (33.3)
Anti-PD-1 or anti-PD-L1	1 (3.3)	1 (3.3)
Anti-CTLA-4	0 (0)	0 (0)
Other immunotherapyb	11 (36.7)	9 (30.0)
Number of previous therapies, n (%)
0	7 (23.3)	7 (23.3)
1	14 (46.7)	15 (50.0)
2	8 (26.7)	5 (16.7)
3	1 (3.3)	1 (3.3)
≥4	0 (0)	2 (6.7)
Setting of regimens before this studyc, n (%)
Adjuvant	3 (10.0)	2 (6.7)
Locally advanced	0 (0)	2 (6.7)
Neoadjuvant	0 (0)	0 (0)
Metastatic	22 (73.3)	22 (73.3)
Previous nephrectomy, n (%)
Yes	29 (96.7)	27 (90.0)
No	1 (3.3)	3 (10.0)

Demographic characteristics were reported from the entrance of this study. For re-randomised patients, the age reported is the age at the time of receiving the re-randomised treatment combination.

CTLA-4, cytotoxic T-lymphocyte-associated protein 4; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; IO, immuno-oncology; IPI, ipilimumab; NIVO, nivolumab; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; RELA, relatlimab; TKI, tyrosine kinase inhibitor.

^aNumber of adverse prognostic factors present (0, 1-2, and 3-6): risk group (favourable, intermediate, and poor).

^bOther than anti-PD-1/anti-PD-L1 or anti-CTLA-4 therapies.

^cMore than one setting per patient may be reflected in the frequency.

Prior systemic therapy was received by 77% of patients in either treatment group. These included TKIs in 53% of patients, PD-1/PD-L1 inhibitors (3%), or immunotherapies other than PD-1/PD-L1 or CTLA-4 inhibitors (37%) in the NIVO + RELA group, and TKIs (60%), PD-1/PD-L1 inhibitors (3%), or immunotherapies other than PD-1/PD-L1 or CTLA-4 inhibitors (30%) in the NIVO + IPI group. The prior PD-1/PD-L1 inhibitors were counted as protocol deviations. There were no significant differences in baseline demographic or disease characteristics between the biomarker-assessable and the total study populations. Demographics for IO-experienced (track 2) patients treated with NIVO + RELA are listed in Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2024.104073.

As of the clinical database lock of 1 November 2021, all patients in the NIVO + RELA and NIVO + IPI groups of track 1 had discontinued study treatment; disease progression was the most common reason for discontinuation in either treatment group [17/30 (57%) and 15/30 (50%) treated patients, respectively; Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2024.104073].

After a median follow-up of 48.6 months (IQR 46.9-51.7 months) for IO-naive patients treated with NIVO + RELA, the proportion of patients with an investigator-assessed objective response was 30% [95% confidence interval (CI) 15% to 49%]. Of 30 patients, 1 (3%) had a complete response, 8 (27%) had a partial response, and 7 (23%) had stable disease, contributing to a disease control rate (DCR) of 53% (95% CI 34% to 72%). The median time to response was 7.9 weeks (Q1-Q3, 7.1-17.0 weeks). The median DOR was 33 weeks (95% CI 16.1-52.6 weeks), with ongoing responses in three (33%) of nine responders in this treatment group. After a median follow-up of 48.7 months (IQR 47.1-52.0 months) for patients treated with NIVO + IPI, the investigator-assessed objective response was 20% (95% CI 8% to 39%). Of 30 patients in this treatment group, 1 (3%) had a complete response, 5 (17%) had a partial response, and 11 (37%) had stable disease, contributing to a DCR of 57% (95% CI 37% to 75%). The median time to response was 8.4 weeks (Q1-Q3 5.7-14.6 weeks). The median DOR was not reached [95% CI 33.4 weeks-not estimable (NE)], with ongoing responses in five (83%) of six responders. Based on the efficacy results summarised above, the prespecified criteria of the objective response required to expand from stage 1 to stage 2 were met in track 1 with NIVO + RELA (nine responders) but not with NIVO + IPI (six responders). Objective response and DCR in all patients treated with NIVO + RELA in track 2 and by LAG-3 and PD-L1 expression are included in the Supplementary Appendix, also see Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2024.104073.

In the NIVO + RELA group, 25 (83%) of 30 patients had a progression event, with median PFS of 4.5 months (95% CI 1.8-7.6 months) and 24-week PFS of 43% (95% CI 25% to 60%; Figure 1). In the NIVO + IPI group, 18 (60%) of 30 patients had a progression event, with a median PFS of 3.4 months (95% CI 2.0-23.7 months) and 24-week PFS of 49% (95% CI 29% to 66%).

Figure 1.

Kaplan–Meier estimates of PFS according to the investigator in all IO-naive patients treated with (A) NIVO + RELA or (B) NIVO + IPI in track 1. Tick marks represent data censored at the last time the patient was known to be alive and free from disease progression. The median PFS was estimated using the Kaplan–Meier method and corresponding 95% CIs were derived based on the Greenwood formula by study treatment under each track. PFS rate was estimated at 24 weeks. CI, confidence interval; IO, immuno-oncology; IPI, ipilimumab; NIVO, nivolumab; PFS, progression-free survival; RELA, relatlimab.

A total of 14 (47%) of 30 patients in the NIVO + RELA treatment group died, with a median OS of 35.6 months (95% CI 19.6 months-NE) and 1-year OS of 82% (95% CI 61% to 92%; Supplementary Figure S3, available at https://doi.org/10.1016/j.esmoop.2024.104073). In the NIVO + IPI treatment group, 12 (40%) of 30 patients had an OS event, with median OS of 38.2 months (95% CI 19.8 months-NE) and 1-year OS of 84% (95% CI 63% to 94%).

Results for IO-experienced patients treated with NIVO + RELA in track 2 are included in the Supplementary Appendix, also see Supplementary Figure S4, available at https://doi.org/10.1016/j.esmoop.2024.104073.

Exploratory biomarker subgroup analyses included patients with measurable LAG-3 and tumour PD-L1 expression at baseline. Biomarker-assessable patient samples comprised 66%-73% of each arm in the full data set. The frequency of patients with LAG-3 and tumour PD-L1 expression ≥1% versus <1% is reported for all assessable track 1 patients in each treatment group (Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2024.104073).

Baseline LAG-3 and PD-L1 expression levels were also assessed in responders versus nonresponders (Supplementary Figure S5, available at https://doi.org/10.1016/j.esmoop.2024.104073). In track 1, a trend toward higher baseline LAG-3 expression levels was observed in responders (n = 7) treated with NIVO + RELA versus nonresponders (n = 15), while no appreciable difference was observed by baseline PD-L1 expression (responders, n = 7; nonresponders, n = 15). In patients treated with NIVO + IPI, nonresponders (n = 14) had numerically higher median baseline LAG-3 expression levels versus responders (n = 6), with no appreciable differences observed by PD-L1 expression (responders, n = 6; nonresponders, n = 15).

In patients treated with NIVO + RELA with measurable LAG-3 expression (≥1% versus <1%), 6 (43%) of 14 versus 1 (13%) of 8 patients had an objective response. Among patients in this treatment group with assessable PD-L1 expression (≥1% versus <1%), 5 (45%) of 11 patients versus 2 (18%) of 11 patients had an objective response (Table 2). In patients treated with NIVO + IPI with measurable LAG-3 expression (≥1% versus <1%), 2 (13%) of 15 patients versus 4 (80%) of 5 had an objective response, respectively. Among patients with assessable PD-L1 expression (≥1% versus <1%), 1 (20%) of 5 versus 5 (31%) of 16 patients had an objective response, respectively.

Table 2.

Objective response, best overall response, and DCR in all IO-naive patients treated with NIVO + RELA or NIVO + IPI in track 1, and by LAG-3 and PD-L1 expression

		NIVO + RELA group (n = 30)	NIVO + IPI group (n = 30)
Objective response, n (%)		9 (30.0)	6 (20.0)
95% CI		14.7-49.4	7.7-38.6
Best overall response, n (%)
Complete response		1 (3.3)	1 (3.3)
Partial response		8 (26.7)	5 (16.7)
Stable disease		7 (23.3)	11 (36.7)
Progressive disease		12 (40.0)	12 (40.0)
Not assessable/available		2 (6.7)	1 (3.3)
Disease control rate, n (%)a		16 (53.3)	17 (56.7)
95% CI		34.3-71.7	37.4-74.5
Patients with measurable LAG-3 expression, n (%); 95% CI
LAG-3 ≥1%	Objective response	n = 14	n = 15
		6 (42.9); 17.7-71.1	2 (13.3); 1.7-40.5
	Disease control ratea	10 (71.4); 41.9-91.6	9 (60.0); 32.3-83.7
LAG-3 <1%	Objective response	n = 8	n = 5
		1 (12.5); 0.3-52.7	4 (80.0); 28.4-99.5
	Disease control ratea	2 (25.0); 3.2-65.1	4 (80.0); 28.4-99.5
Patients with measurable tumour PD-L1 expression, n (%); 95% CI
PD-L1 ≥1%	Objective response	n = 11	n = 5
		5 (45.5); 16.7-76.6	1 (20.0); 0.5-71.6
	Disease control ratea	8 (72.7); 39.0-94.0	2 (40.0); 5.3-85.3
PD-L1 <1%	Objective response	n = 11	n = 16
		2 (18.2); 2.3-51.8	5 (31.2); 11.0-58.7
	Disease control ratea	4 (36.4); 10.9-69.2	11 (68.8); 41.3-89.0

Objective response and best overall response were assessed per investigator using RECIST version 1.1. Objective responses and corresponding two-sided exact 95% CIs were based on the Clopper–Pearson method by study treatment under each track.

CI, confidence interval; DCR, disease control rate; IO, immuno-oncology; IPI, ipilimumab; LAG-3, lymphocyte activation gene 3; NIVO, nivolumab; PD-L1, programmed death-ligand 1; RELA, relatlimab.

^aProportion of patients with the best overall response of complete response, partial response, or stable disease.

In the NIVO + RELA group, the median PFS was 6.4 months (95% CI 1.9-10.3 months) versus 1.6 months (95% CI 0.5-6.2 months) in patients with assessable LAG-3 expression (≥1% versus <1%) and 6.4 months (95% CI 1.2-13.7 months) versus 1.8 months (95% CI 1.3-6.2 months) in patients with assessable tumour PD-L1 expression (≥1% versus <1%; Figure 2). In the NIVO + IPI group, the median PFS (95% CI) was 8.8 months (95% CI 2.0 months-NE) versus not reached (95% CI 1.4 months-NE) in patients with assessable LAG-3 expression (≥1% versus <1%) and 2.6 months (95% CI 1.9 months-NE) versus 9.6 months (95% CI 1.9 months-NE) in patients with assessable tumour PD-L1 expression (≥1% versus <1%; Figure 2). OS by LAG-3 and PD-L1 expression is reported in Supplementary Figure S6, available at https://doi.org/10.1016/j.esmoop.2024.104073.

Figure 2.

Kaplan–Meier estimates of PFS by (A, C) LAG-3 or (B, D) PD-L1 expression according to the investigator in assessable IO-naive patients treated with NIVO + RELA or NIVO + IPI in track 1. IO, immuno-oncology; IPI, ipilimumab; LAG-3, lymphocyte activation gene 3; NE, not estimable; NIVO, nivolumab; NR, not reached; PD-L1, programmed death-ligand 1; RELA, relatlimab.

Results for biomarker analyses in patients treated with NIVO + RELA in track 2 are included in Supplementary Figures S5-S7, available at https://doi.org/10.1016/j.esmoop.2024.104073.

In track 1, 24 (80%) of 30 patients treated with NIVO + RELA had a treatment-related AE of any grade, and grade ≥3 treatment-related AEs occurred in 4 (13%) of 30 patients (Figure 3). Treatment-related AEs of any grade led to discontinuation in 3 (10%) of 30 patients. In the NIVO + IPI group, 25 (83%) of 30 patients had a treatment-related AE of any grade, and grade ≥3 treatment-related AEs occurred in 10 (33%) of 30 patients. Treatment-related AEs of any grade led to discontinuation in 5 (17%) of 30 patients in this group. No deaths were attributed to study treatment in either group. Treatment-related immune-mediated AEs by category are listed in Supplementary Table S4, available at https://doi.org/10.1016/j.esmoop.2024.104073. Safety results for IO-experienced (track 2) patients treated with NIVO + RELA are listed in Supplementary Table S5, available at https://doi.org/10.1016/j.esmoop.2024.104073.

Figure 3.

Treatment-related AEs in all IO-naive patients treated with NIVO + RELA or NIVO + IPI in track 1. ^aIncludes events reported between the first dose and 100 days after the last dose of study therapy. Any-grade events in ≥10% of patients in either arm. AE, adverse event; IO, immuno-oncology; IPI, ipilimumab; NIVO, nivolumab; RELA, relatlimab.

Discussion

FRACTION-RCC is a phase II adaptive trial that evaluated the efficacy and safety of IO-based treatment combinations in patients with advanced clear cell RCC. The current analysis focused on IO-naive (track 1) patients treated with NIVO + RELA or NIVO + IPI, although the study was not designed to make direct comparisons between arms. Analyses in IO-experienced (track 2) patients treated with NIVO + RELA are included for completeness. Results from this study showed antitumour activity in IO-naive patients treated with combination immunotherapy, although >50% of patients had received previous antivascular endothelial growth factor therapy in either arm. In the NIVO + RELA group, patients achieved an objective response per investigator of 30%, with a 43% PFS rate at 24 weeks. In the NIVO + IPI group, 20% of patients responded to treatment, with a 49% PFS rate at 24 weeks. We also observed differences in antitumour effects in exploratory subgroups by LAG-3 and PD-L1 expression. The safety profiles of NIVO + RELA and NIVO + IPI were consistent with previous reports for each combination, with no unexpected safety signals or treatment-related deaths in either group.

IO-based therapies targeting immune checkpoints have reshaped first- and second-line therapy for many patients living with aRCC by providing improved durability of response and long-term survival, even beyond 5 years.^1,3,6,7,23, 24, 25 The exceptional clinical benefit found with checkpoint inhibitor immunotherapies such as NIVO + IPI, pembrolizumab + axitinib, NIVO + cabozantinib, and pembrolizumab + lenvatinib has been met with approvals for the treatment of patients with aRCC in countries worldwide.6, 7, 8^,10 However, despite significant improvements in efficacy and widespread approvals, a proportion of patients still do not respond to available IO-based combinations with anti-CTLA-4 and anti-PD-1/PD-L1 monoclonal antibodies, especially in the second-line setting.^3,6,7,23,26, 27, 28 While an increasing number of immune checkpoint proteins have been screened for effectiveness in preclinical and clinical trials, a need remains for novel and innovative regimens to increase the number of patients who derive long-term benefits. LAG-3 is part of the second wave of immunotherapy targets showing promise for use in the treatment of solid tumours including clear cell RCC.

Higher LAG-3 expression, at both messenger RNA and protein levels, is reported to be associated with worse clinical outcomes in clear cell RCC.^29,30 LAG-3 acts in a nonredundant manner from the PD-1 pathway to suppress T-cell stimulation,¹⁹ and recent preclinical data have shown cooperation between LAG-3 and PD-1 inhibitory receptors in maintaining immune regulation and mediating tumour-induced tolerance.^15,19 LAG-3 upregulation has also been associated with acquired resistance to PD-1 inhibitors and may reflect loss of T-cell effector function.³¹ As such, targeting LAG-3 via combination immunotherapy is being assessed as a potential approach for overcoming resistance to immune checkpoint blockade.

RELA is a novel, first-in-class human immunoglobulin G4 checkpoint inhibitor of LAG-3, which is found on the surface of T cells and is often upregulated in melanoma.^14,19,32 In preclinical studies, dual PD-1 and LAG-3 inhibition with the NIVO + RELA combination has shown synergistic antitumour effects, and RELA (in combination with NIVO) has since become the first LAG-3-blocking antibody to demonstrate a benefit in a phase III trial.^14,15,19 In RELATIVITY-047, a phase II/III, randomised, double-blind clinical trial in patients with previously untreated metastatic or unresectable stage III or IV melanoma, combination immunotherapy with NIVO + RELA demonstrated a statistically significant improvement in PFS versus NIVO alone (hazard ratio 0.75, 95% CI 0.62-0.92; P = 0.006).¹⁴ Based on these results, the combination of NIVO + RELA was approved by the FDA in 2022 for the treatment of unresectable or metastatic melanoma in patients ≥12 years of age and by the European Commission in 2022 for the first-line treatment of advanced melanoma in patients ≥12 years of age with tumour PD-L1 expression <1%.¹⁴

These analyses from FRACTION-RCC investigated antitumour effects with NIVO + RELA and NIVO + IPI in patients with aRCC. As FRACTION-RCC is largely a second-line study, objective response can be expected to be lower relative to first-line regimens.³

Although the response rate for patients treated with NIVO + IPI was lower in FRACTION-RCC (20%; 95% CI 8% to 39%) than reported in CheckMate 214 (39%; 95% CI 35% to 44%), CIs were markedly wide in FRACTION-RCC due in part to the small treatment groups, and the study populations were distinct.³³ Patients in track 1 of FRACTION-RCC were naive to treatment with IO-based combination therapy, yet most were more advanced in terms of treatment experience, with 77% of patients having received previous therapy, versus the treatment-naive population assessed in CheckMate 214.³³ Findings from the NIVO + IPI group in FRACTION-RCC were, however, consistent with regard to durability, with positive results from larger clinical trials of this combination in patients with aRCC such as CheckMate 214, which has since demonstrated long-term survival and durable response benefits with the combination versus sunitinib.^3,9,33 As a whole, outcomes reported in FRACTION-RCC continue to add to the wealth of data reported for NIVO + IPI as a standard of care in first-line aRCC, including ongoing responses with combination immunotherapy observed in both treatment arms.

Exploratory biomarker assessments were conducted to evaluate the association of biomarkers with clinical outcomes and provide insight into baseline immunobiology that could be linked to drug activity. As previously reported in melanoma, there appeared to be higher antitumour activity with NIVO + RELA among biomarker-assessable patients with LAG-3 or PD-L1 expression ≥1% (Figure 2).¹⁴ Interestingly, in another phase I/II trial evaluating a combination of anti-LAG-3 and anti-PD-1 antibodies across solid tumours, including RCC, there was no observed association between baseline LAG-3 protein expression and clinical response; however, higher LAG-3 gene expression was reported to be associated with treatment response.³⁴ In the NIVO + IPI group of this analysis, biomarker subgroup results indicate that higher LAG-3 or PD-L1 expression may be associated with worse PFS. These results should be interpreted with further caution; notwithstanding the limited overall patient numbers, the analysis is also constrained by small biomarker subgroup numbers (range of patient numbers in subgroup analyses, n = 5 to 16).

Unlike in some other solid tumours, there are no PD-L1 expression-based restrictions for treating clear cell RCC with IO or IO in combination with other interventions.^3,35,36 Published data on LAG-3 expression and its association with clinical outcomes in clear cell RCC are diverse and a greater understanding of this relationship is still evolving. Schoenfeld et al.³⁷ assessed LAG-3 protein levels in primary RCC tumours versus matched metastatic tumours and observed that LAG-3 protein levels were on average higher in primary sites versus matched metastatic sites. Interestingly, relatively higher levels of LAG-3 expression within metastatic sites were associated with improved response to immunotherapy, as well as better OS and DCRs.³⁷ In FRACTION-RCC, IO-naive responders treated with NIVO + RELA in track 1 trended toward higher median baseline LAG-3 expression levels versus nonresponders (Supplementary Figure S5, available at https://doi.org/10.1016/j.esmoop.2024.104073). There was no appreciable difference in median PD-L1 expression at baseline among responders versus nonresponders. More comprehensive biomarker assessments of primary kidney tumours and metastatic sites, including composite assessments and gene expression-based clustering,³⁸ may help to build on these observations.

A limitation of our analysis is the small dataset for the overall treatment arms and relatively low numbers of patients with assessable biomarker expression for subgroup analyses. Due in part to the low number of patients in the FRACTION-RCC analysis, the data reported here are descriptive and hypothesis-generating for further exploration. Larger cohorts of patients with aRCC are needed for future clinical trials of RELA-based combination therapies to evaluate if tumour expression of LAG-3 alone or in combination with other biomarkers is associated with improved survival and response benefits.

In summary, we report a phase II trial investigating dual checkpoint inhibition of PD-1 combined with either LAG-3 or CTLA-4. FRACTION-RCC was designed to evaluate multiple IO treatment combinations via a continuous throughput and adaptive study design. The goal was to reduce the time and number of patients required to determine the most effective combinations of IO agents and to bring novel therapies more rapidly to patients with high unmet medical needs who would benefit from them. These results show antitumour activity and manageable safety with NIVO in combination with RELA in patients with aRCC and support previous studies demonstrating the use of NIVO + IPI as an effective treatment option in patients with aRCC.^3,25 Further evaluation of NIVO + RELA in larger populations of patients with aRCC and in conjunction with additional biomarker analyses are needed to support these preliminary findings, and to generate hypotheses around potential patient selection strategies using biomarkers.

Disclosure

TKC reports consulting or advisory roles outside the submitted work with Alkermes, Arcus Bio, AstraZeneca, Aravive, AVEO, Bayer, Bristol Myers Squibb (BMS), Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVIA, Infinity, Ipsen, Janssen, Kanaph, Lilly, Merck, NiKang, Neomorph, Nuscan/PrecedeBio, Novartis, OncoHost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events (PeerView, OncLive, MJH, CCO, and others); honoraria and/or transport and meals related to meetings, lectures, and advisory boards from Alkermes, AstraZeneca, Aravive, AVEO, Bayer, BMS, Calithera, Circle Pharma, Deciphera Pharmaceuticals, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, Gilead, HiberCell, IQVIA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, NiKang, Neomorph, Nuscan/PrecedeBio, Novartis, OncoHost, Pfizer, Roche, Sanofi/Aventis, Scholar Rock, Surface Oncology, Takeda, Tempest, Up-To-Date, and CME events (PeerView, OncLive, MJH, CCO, and others); participation on a data safety monitoring board with Aravive; leadership role with KindeyCan (nonfinancial), and committees for ASCO/ESMO/NCCN/GU Steering Committee of the NCI; stock ownership with Pionyr, Tempest, Precede Bio, Osel, Curesponse, InnDura Therapeutics, and Primium; other financial interests with support in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, Pan-Mass Challenge, Hinda and Arthur Marcus Fund and Loker Pinard Funds for Kidney Cancer Research at DFCI. TMK reports consulting or advisory roles with CVS, Kyowa Hakko Kirin, AbbVie, Emmaus Medical Inc., Cardinal Health, Merck, and BMS/SeaGent/Fida Therapeutics/Engene/Medpace; honoraria from BMS; travel support from Cardinal Health; and research funding to the institution from Genentech/Roche, Eisai, BMS, and Seattle Genetics. SST reports consulting or advisory roles with FirstWord, AVEO Oncology, Exelixis, and Merck; honoraria from OncLive, Targeted Oncology, and Cancer Network; travel, accommodations, and expenses from DAVA Oncology; medical writing support from BMS; research funding to the institution from Xencor, Merck, AVEO Oncology, BMS, Exelixis, Pfizer, Nektar Therapeutics, Iovance Biotherapeutics, and Genentech; and royalties or licenses from a patent pending. HK reports consulting or advisory roles with Iovance, Merck, ChemoCentryx, BMS, Signatera, GigaGen, GI reviewers, Pliant Therapeutics, Eisai, Invox, and Werewolf; honoraria from Merck; and grants to the institution from BMS, Merck, and Apexigen. RP reports consulting or advisory roles with Galmed, Gilboa, and 1E Therapeutics; honoraria from GSK and MSD; and travel, accommodations, and expenses from MSD. SGe reports consulting or advisory roles with BMS, Bayer, Pfizer, Exelixis, Corvus Pharmaceuticals, Sanofi, EMD Serono, Seattle Genetics/Astellas, Eisai, Merck, AVEO, and QED Therapeutics; travel, accommodations, and expenses from BMS/Medarex and Sanofi; and research funding to the institution from Pfizer, Merck, Agensys, Novartis, BMS, Bayer, Eisai, Seattle Genetics/Astellas, Surface Oncology, Exelixis, Aravive, AVEO, and Gilead Sciences. HG reports consulting or advisory roles with BMS, Ipsen, Merck Sharp & Dohme, AstraZeneca, Janssen-Cilag, Pfizer, Roche, Merck Serono, Astellas Pharma; and honoraria from Merck Serono and AstraZeneca. RKP reports consulting or advisory roles with EMD Serono, BMS, Pfizer/EMD Serono, Sanofi, Jounce Therapeutics, Dendreon, Bayer, Genomic Health, and Blue Earth Diagnostics; honoraria from Dendreon, Merck, Genentech/Roche, AstraZeneca, Sanofi, Genomic Health; travel, accommodations, and expenses from Genentech/Roche; research funding to the institution from Pharmacyclics, BMS Foundation, and Exelixis; research funding to self from Janssen Oncology; and patents pending from Method of Cell-Free DNA Analysis to Identify High Risk Metastatic Prostate Cancer. VC reports consulting or advisory roles with Ipsen, Eisai, Merck, AstraZeneca, Pfizer, Novartis, BMS, Astellas, and Janssen. CHL reports consulting or advisory roles with Amgen, BMS, Exelixis, Eisai, Merck, Pfizer, and EMD Serono; honoraria from AiCME, Intellisphere, and Research to Practice; grants (institution) from BMS, Calithera, Eisai, Eli Lilly, Exelixis, Merck, and Pfizer; and stock ownership with Exelixis and BMS. UV reports consulting or advisory roles with BMS, Alkermes, AVEO, Bayer, Exelixis, Gilead, and Aadi; honoraria from BMS, Exelixis, and Bayer; leadership or fiduciary role with MI Soc Hematology Oncology (board member); research funding to the institution from Datar Inc and Roche Inc; grants to the institution from Merck and BMS (research support); and writing support (nonfinancial) from BMS. WHM reports consulting or advisory roles with BMS, Merck, Roche, Novartis, GSK, Amgen, Mylan, EMD Serono, and Sanofi; honoraria from BMS, Merck, Roche, Novartis, GSK, Sanofi, Mylan, and EMD Serono; research funding to the institution from Merck, BMS, Novartis, GSK, Roche, AstraZeneca, MethylGene, MedImmune, Sanofi, Array, MiMic, Ocellaris, Astellas, Pfizer, Genentech, and Seagen; and grants to the institution from CIHR, CRS, and SWCRF. PB, YW, HD, and CWL report employment and stock ownership with BMS. SGu reports employment and stock ownership with BMS (self and immediate family members). BE reports consulting or advisory roles with Pfizer, BMS, Ipsen, AVEO, and Oncorena; honoraria from Pfizer, BMS, Ipsen, and Oncorena; travel, accommodations, and expenses from BMS, Ipsen, and MSD; and research funding to the institution from BMS. RJM reports consulting or advisory roles with Eisai, Exelixis, Merck, Genentech/Roche, Incyte, Pfizer, AstraZeneca, EMD Serono, Calithera Biosciences, AVEO, and Takeda; travel, accommodations, and expenses from BMS; and research funding to the institution from Pfizer, BMS, Eisai, Novartis, Genentech/Roche, Exelixis, Merck, and AVEO. All other authors have declared no conflict of interest.