Adding relatlimab to nivolumab (a combination known as Opdualag) plus platinum-doublet chemotherapy demonstrated improved clinical benefit compared with nivolumab (Opdivo) plus chemotherapy in patients with stage IV or recurrent non–small cell lung cancer (NSCLC), according to findings from the phase 2 RELATIVITY-104 study (NCT04623775) presented at the 

These findings were shown in patients with PD-L1 of at least 1%, and further enriched in patients with nonsquamous histology.

“RELATIVITY-104 is the first proof-of-concept, randomized phase 2 study in metastatic NSCLC that demonstrated improved clinical benefit from the addition of LAG3 inhibition to anti–PD-1 [inhibition] plus chemotherapy in the PD-L1–positive stratified and prespecified patient subgroup, which was further enriched with nonsquamous cell histology,” Nicolas Girard, MD, PhD, head of the Curie-Montsouris Thorax Institute and professor of respiratory medicine at Versailles Saint Quentin University Paris Saclay Campus in Paris, France, said during the presentation.

After a median follow-up of 10.7 months, 24% of patients in the relatlimab plus nivolumab and chemotherapy group (n = 38) and 30% of those in the nivolumab plus platinum-doublet chemotherapy group (n = 44) were still receiving study treatment. Safety was comparable between both arms, with grade 3 or 4 treatment-related adverse effects (TRAEs) occurring in 54% (n = 86) of patients in the relatlimab-based therapy arm vs 55% (n = 82) in the nivolumab plus chemotherapy arm. Any-grade TRAEs leading to discontinuation occurred in 13% (n = 21) in the relatlimab group compared with 14% (n = 21) in the nivolumab plus chemotherapy group. Grade 3 or higher treatment-related neutropenic AEs were observed in 6% of patients in the relatlimab arm vs 14% in the nivolumab plus chemotherapy group.

“The safety profile of nivolumab plus relatlimab 360 mg plus platinum-doublet chemotherapy was consistent with the known profile of the individual components of the combination and showed no increase in adverse effects rates vs nivolumab plus chemotherapy,” Girard said.

Six patients in the relatlimab group died from TRAEs including neutropenic sepsis (n = 2), febrile neutropenia (n = 1), pneumonitis (n = 2), and pneumonia (n = 1). Five patients died in the nivolumab plus chemotherapy group due to febrile neutropenia, sepsis, septic shock, asthenia, and lung disorder, occurring in 1 patient each.

The most common TRAEs, occurring in at least 20% of patients treated with the relatlimab-based treatment included nausea, anemia, neutropenia, fatigue, and thrombocytopenia.

Efficacy was assessed in all patients in the trial randomized to either relatlimab plus nivolumab and chemotherapy (n = 158) or nivolumab plus chemotherapy (n = 151). The HR for progression-free survival (PFS) was 0.88 (90% CI, 0.71-1.11), slightly favoring treatment with relatlimab plus nivolumab plus chemotherapy compared with nivolumab plus chemotherapy. The median PFS for each group was 6.7 months (90% CI, 5.6-8.4) and 6.0 months (90% CI, 5.5-6.9), respectively.

There was also a moderate improvement in overall response rate (ORR) with relatlimab plus nivolumab and chemotherapy compared with nivolumab plus chemotherapy (51.3% vs 43.7%, respectively; difference = 7.6%). The median duration of response was 10.1 months in the relatlimab plus nivolumab and chemotherapy group vs 9.1 months in the nivolumab plus chemotherapy group.

Girard noted that data on overall survival were not yet mature at this follow-up.

In stratified patient subgroups, patients with a PD-L1 expression of 1% or higher had improved PFS and response rates with the relatlimab-based treatment. The median PFS was 9.8 months (90% CI, 5.9-13.8) in the relatlimab group vs 6.1 (90% CI, 4.2-7.0) in the nivolumab plus chemotherapy group (HR, 0.63; 90% CI, 0.45-0.88). The ORR was 53.2% (90% CI, 43.3%-62.8%) and 40.8% (90% CI, 31.0%-51.3%), respectively.

“We do not see this trend in PD-L1–negative tumors,” Girard said.

When assessed by histology, the benefit derived from relatlimab plus nivolumab and chemotherapy compared with nivolumab plus chemotherapy was further enhanced in patients with nonsquamous cell histology, with a median PFS of 8.3 months (90% CI, 5.6-9.8) vs 6.0 months (90% CI, 4.6-7.0), respectively (HR, 0.86; 90% CI, 0.64-1.13).

In patients with squamous cell histology, response rate and PFS were "somewhat similar,” Girard added.

Researchers then took into consideration the individual trends seen by PD-L1 expression and histology. “We see that the addition of relatlimab to nivolumab plus chemotherapy clearly favor,” Girard said.

In this analysis, PFS is improved with the addition of relatlimab to nivolumab plus chemotherapy vs nivolumab plus chemotherapy, with a median PFS of 11.6 months (90% CI, 6.9-NR) and 6.9 months (90% CI, 4.2-7.1), respectively (HR, 0.55; 90% CI, 0.36-0.85).

Similar improvements were seen in responses to treatment, with a 58.0% response rate in the relatlimab-based treatment and 39.6% in the nivolumab plus chemotherapy group (difference = 18.4%). The median duration of response was 13.8 months vs 12.6 months, respectively.

“These data provide the rationale for further investigation in a phase 3 study,” Girard said.

Patients also benefitted from treatment with the relatlimab-based therapy in PD-L1 expressions between 1% and 49% and nonsquamous cell histology in terms of PFS (HR, 0.45; 90% CI, 0.25-0.81). The response rate for each group was 60.7% and 30.0%, respectively (difference = 30.7%).

Patients with a PD-L1 expression of 50% and higher, in addition to nonsquamous cell histology also demonstrated an improved median PFS with the relatlimab-based treatment vs the nivolumab plus chemotherapy treatment (13.8 months vs 7.1 months; HR, 0.60; 90% CI, 0.31-1.15).

“The difference in overall response rate was more moderate than in the 1% to 49% PD-L1 expression cases, but still, with [nivolumab] plus [relatlimab] plus platinum-doublet chemotherapy, we see a 55% response rate in the subgroup of patients,” Girard said.

Relatlimab is a human LAG3-blocking antibody that restores effector T-cell function, Girard explained.

He added, “The inhibition of PD-1 and LAG3 with nivolumab plus relatlimab further improves anti-tumor immune response with an effect that is greater than that of either antibody alone. This combination was approved for the treatment of advanced melanoma.”

Part 2 of the RELATIVITY-104 study, which was reported during this presentation, aimed to identify patient populations with metastatic NSCLC who might benefit from the addition of relatlimab. In particular, 309 patients with treatment-naive stage IV/recurrent NSCLC, no driver alterations, and an ECOG performance status of 0 or 1. Patients were randomized 1:1 to receive 360 mg of nivolumab, 360 mg of relatlimab, and platinum-doublet chemotherapy every 3 weeks, or 360 mg of nivolumab plus chemotherapy. Patients in the trial were stratified by tumor PD-L1, histology, and ECOG performance score.

The primary end point of the study was ORR by blinded independent committee review. Secondary end points included PFS, efficacy by PD-L1 status, and safety.

Girard mentioned RELATIVITY-1093 (NCT06561386), an open-label, randomized phase 3 study that will evaluate nivolumab plus relatlimab and platinum-doublet chemotherapy compared with standard-of-care pembrolizumab (Keytruda) plus chemotherapy as first-line treatment of patients with metastatic NSCLC with a PD-L1 expression between 1% and 49% and nonsquamous cell histology.

Girard N, Burotto M, Paz-Ares LG. Nivolumab (NIVO) plus relatlimab with platinum-doublet chemotherapy (PDCT) vs NIVO + PDCT as first-line (1L) treatment (tx) for stage IV or recurrent NSCLC: Results from the randomized phase II RELATIVITY-104 study. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract LBA53.

Articles

Findings from the phase 2 RELATIVITY-104 study demonstrates a clinical benefit with the addition of relatlimab to nivolumab and chemotherapy. 

Relatlimab Plus Nivolumab and Chemo Improves Clinical Benefit in Stage IV NSCLC

The 1-year survival difference between patients with stage IV non-small cell lung cancer (NSCLC) treated with either a standard or reduced dose of pembrolizumab (Keytruda) met the established criteria for continued enrollment of the NVALT-30 trial (NCT04909684), according to recent study findings presented at the 

“There’s a notion that trials on the optimization of dosing, duration, and personalization of treatment are really underrepresented in the current research,” Michel M van den Heuvel, a professor at the Radboud Institute for Molecular Life Sciences in Nijmegen, Netherlands, said during the presentation.

The 1-year overall survival rate was 57.7% (95% CI, 49.5%-67.3%) in the standard-dose group and 55.0% (95% CI, 47.0%-64.4%) in the reduced dose group. Median overall survival was 17.0 months (95% CI, 11.8-23.2) in the standard-dose group and 13.9 months (95% CI, 10.8-16.9) in the reduced-dose group. There was no significant difference in overall survival between the groups (

Median progression-free survival was 6.9 months (95% CI, 6.0-9.8) in the standard-dose group compared with 7.6 months (95% CI, 5.8-11.3) in the reduced-dose groups.

In addition, the 1-year disease control rate was 37% (95% CI, 29.2%-46.7%) in the standard-dose arm and 39.2% (95% CI, 31.6%-48.7%) in the reduced-dose arm. The objective response rate was 50.9% (95% CI, 41.3%-60.4%) in patients assigned the standard dose vs 54.5% (95% CI, 45.2-63.6%) in those assigned the reduced dose.

Researchers performed an open-label, non-inferiority trial to compare either the standard dose (n = 123; median age, 69 years; 59% men) or reduced dose (n = 133; median age, 68 years; 58% men) of pembrolizumab. Patients in the standard-dose group received pembrolizumab either 400 mg every 6 weeks, 150 mg every 3 weeks, or 200 mg every 3 weeks. For patients in the reduced-dose group, patients received 300 mg every 6 weeks or 100 mg every 3 weeks.

“The primary objective of this study is to investigate the non-inferiority of reduced-dose pembrolizumab vs standard of treatment of advanced stage non-small cell lung cancer in terms of overall survival,” van den Heuvel said.

The trial enrolled patients with NSCLC who were eligible for pembrolizumab-based treatment. An interim analysis was planned after the first 250 patients were enrolled and then followed for 1 year. A difference of 10% in 1-year overall survival between the groups was considered clinically significant and may lead to early termination of the trial.

Secondary objectives of the study included disease control rate, progression-free survival, 1-year disease control rate, overall response rate, and to develop, assess, and validate immune checkpoint inhibitor response biomarkers.

The median cumulative dose of pembrolizumab was 1600 mg in the standard-dose arm compared with 1200 in the reduced-dose arm. Thirty-four percent of patients assigned the standard dose arm were still on treatment after 1 year compared with 28% assigned the reduced dose. The most common reason for treatment termination was progressive disease, van den Heuvel noted.

As immunotherapy is the “backbone of treatment of non-small cell lung cancer,” as van den Heuvel noted, it has its disadvantages despite improving survival and quality of life. One of these disadvantages is the fact that the response rate is nearly 50%.

“The toxicity is also, although acceptable and manageable, sometimes worrisome, and bothersome especially the long-term toxicity,” said van den Heuvel. “In fact, limited data on the optimal dosing, as we know from all types of ex vivo models, we see that there is a clear dose relation.”

There are several current standard-of-care doses of Keytruda, including 200 mg every 3 weeks, 400 mg every 6 weeks, and 150 mg every 3 weeks, among others.

“But could we improve on this dosing and, thereby, for instance, reduce healthcare costs and maybe redundant exposure to pembrolizumab,” van den Heuvel said.

Van den Heuvel, M., Van der Noort, V., Ter Heine, R., et al. (2024). Low dose versus standard dose pembrolizumab for treatment of stage IV non-small cell lung carcinoma: Results of the pre-planned interim analysis of the NVALT-30 clinical trial. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract 1258MO

A lower dose of pembrolizumab may be as effective as the standard dose for treating stage IV non-small cell lung cancer. 

Low-Dose Pembrolizumab May Prove Equal Efficacy as a Standard Dose for Stage IV NSCLC

Longer follow-up data continues to demonstrate a promising overall survival (OS) trend with amivantamab (Rybrevant) plus chemotherapy vs chemotherapy alone in patients with 

-mutant advanced non-small cell lung cancer (NSCLC) who experienced disease progressed on osimertinib (Tagrisso), according to findings from the second interim analysis of the phase 3 MARIPOSA-2 trial (NCT04988295).

Results from a median follow-up of 18.1 months were presented at the 

“Indeed, amivantamab’s multi-targeted mechanism of action and immune cell-directed activity, combined with chemotherapy's nonspecific anti-tumor effects, likely contributes to this observed durability,” Sanjay Popat, BSc, MBBS, FRCP, PhD, consultant medical oncologist at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research in London, said during the presentation of the data.

Amivantamab plus chemotherapy continued to demonstrate a meaningful and improved OS trend compared with chemotherapy, although it did not reach statistical significance. Patients assigned amivantamab plus chemotherapy had a median OS of 17.7 months (95% CI, 16.0-22.4) compared with 15.3 months (95% CI, 13.7-16.8) in patients assigned chemotherapy alone (HR = 0.73; 95% CI, 0.54-0.99; 

 = .039). OS was 50% for the amivantamab plus chemotherapy group vs 40% in the chemotherapy alone group.

“The curves separate after 6 months of follow-up and continue to separate thereafter, with an absolute survival difference of 7% at the 12-month landmark, 70% vs 63%, increasing to 10 months at the 18-month landmark of 50% vs 40%,” Popat said. “MARIPOSA-2 is ongoing and will proceed to final overall survival analysis, as planned.”

Time to symptomatic progression (TTSP) was significantly improved in patients treated with amivantamab plus chemotherapy compared with chemotherapy, with rates at 43% and 34%, respectively. The median TTSP was 16.0 months (95% CI, 12.7-19.4) in the amivantamab plus chemotherapy group and 11.8 months (95% CI, 8.9-13.6) in the chemotherapy group (HR = 0.73; 95% CI, 0.55-0.96; 

 = .026). This represented a 27% reduction in the risk for symptomatic progression with amivantamab plus chemotherapy vs chemotherapy alone.

“Exploratory endpoints included time to symptomatic progression, which is clinically meaningful, as this captures not only radiographic progression, but also symptomatic progression, defined as time from randomization until deterioration of lung cancer-associated symptoms or new symptoms resulting in clinical change in systemic therapy,” Popat said.

Time to treatment discontinuation (TTD) was also significantly prolonged with amivantamab plus chemotherapy compared with chemotherapy alone (22% vs 4%, respectively).

“Time to treatment discontinuation, again, remains a meaningful endpoint in clinical practice, as this captures the additional time beyond progression of systemic therapy,” Popat said.

The median TTD was 10.4 months (95% CI, 7.9-11.6) and 4.5 months (95% CI, 4.2-5.0), respectively (HR = 0.42; 95% CI, 0.33-0.53; 

“Indeed, at the 18-month landmark, 5-fold more patients remained on treatment with a combination of amivantamab-chemotherapy than chemotherapy alone,” Popat added.

In addition, time to subsequent therapy (TTST) was also significantly prolonged with amivantamab plus chemotherapy compared with chemotherapy alone (31% vs 12%, respectively).

“Time to subsequent therapy is an important landmark endpoint, insofar as it captures time from randomization until commencement of next line of systemic therapy in those that commence it, and is important for our reimbursement agencies,” Popat explained.

The median TTST was 12.2 months (95% CI, 10.7-14.3) in patients treated with amivantamab plus chemotherapy compared with 6.6 months (95% CI, 6.1-7.4) in those treated with chemotherapy alone (HR = 0.51; 95% CI, 0.39-0.65; 

“TTST was 2-fold longer with the combination than chemotherapy,” Popat said.

Regarding first subsequent therapy, fewer patients in the amivantamab-chemotherapy arm had disease progression compared with the chemotherapy arm (68% vs 83%). Most patients in both groups went on to receive a subsequent therapy.

Popat noted that in both groups, there was a diversity of subsequent therapies used, including a tyrosine kinase inhibitor (TKI) combination, other TKIs, osimertinib or other third-generation TKIs, and others.

“We see that there is no clear single therapy class identified as the most prominent subsequent therapy, reiterating that most patients in this third-line setting are often re-exposed to previously used therapies, highlighting the importance of maximizing not only first but also second-line treatment duration,” he explained.

Progression-free survival after first subsequent therapy (PFS2) was significantly prolonged with amivantamab plus chemotherapy vs chemotherapy alone. At 18 months, the PFS2 rate was 39% vs 27%, respectively. The median PFS2 was 16.0 months (95% CI, 13.9-17.6) in the amivantamab plus chemotherapy arm compared with 11.6 months (95% CI, 10.1-13.0) in the chemotherapy alone arm (HR = 0.64; 95% CI, 0.48-0.85; 

Popat explained that progression on or after TKI monotherapy is “nearly inevitable, with resistance mechanisms that can be diverse and mostly polyclonal.”

At the 2023 ESMO Congress, findings were presented that demonstrated that at a median follow-up of 8.7 months, the trial met its primary endpoint, as amivantamab plus chemotherapy significantly improved PFS compared with chemotherapy in patients with 

-mutant advanced NSCLC after disease progression on osimertinib (HR = 0.48; 95% CI, 0.36-0.64; 

 Combination treatment also showed a favorable trend for OS (HR = 0.77; 95% CI, 0.49-1.21) at the first interim OS analysis.

Popat noted that amivantamab plus chemotherapy is currently EMA approved and currently pending FDA approval to treat patients with 

-mutant advanced NSCLC after disease progression on an EGFR TKI.

Patients were eligible for the MARIPOSA-2 trial if they had locally advanced or metastatic EGFR-mutated NSCLC with documented 

exon 19 deletion or L858R and whose disease progressed on or after osimertinib monotherapy as the most recent line of therapy. Patients also had to have good performance status, with an ECOG performance score of 0 or 1.

In this trial, 657 patients were randomized 2:1:1 to either receive amivantamab plus lazertinib (Lazcluze) and chemotherapy (n = 263), chemotherapy alone (n = 362), or amivantamab plus chemotherapy (n = 131).

“The focus of this presentation will be on the latter 2 arms, specifically chemotherapy or amivantamab-chemotherapy,” Popat explained.

Secondary/exploratory efficacy endpoints reported in this trial included OS, TTSP, TTD, TTST, and PFS2.

“The second interim overall survival analysis was prespecified when 75% of the planned overall survival events were observed,” Popat said.

For this second interim analysis for OS, the significance level was determined based on the O’Brien-Fleming alpha spending approach (2-sided alpha = 0.0142), as implemented by the Lan-DeMets method.

Popat S, Reckamp KL, Califano R, et al. Amivantamab plus chemotherapy vs chemotherapy in EGFR-mutated, advanced non-small cell lung cancer after disease progression on osimertinib: Second interim overall survival from MARIPOSA-2. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Presentation LBA54.

Gentzler RD, Spira A, Melosky B, et al. Amivantamab plus chemotherapy vs chemotherapy in EGFR-mutant advanced NSCLC after progression on osimertinib: a post-progression analysis of MARIPOSA-2. 

. 2024;9(suppl 3):1-53. doi:10.1016/esmoop/esmoop102569

Amivantamab plus chemotherapy yielded promising OS trends compared with chemotherapy in EGFR-mutant advanced NSCLC after disease progression on osimertinib. 

Spencer Feldman

Articles

Relatlimab Plus Nivolumab and Chemo Improves Clinical Benefit in Stage IV NSCLC

Low-Dose Pembrolizumab May Prove Equal Efficacy as a Standard Dose for Stage IV NSCLC

Longer Follow-Up Confirms Superior Outcomes With Amivantamab Plus Chemo in EGFR-Mutant Advanced NSCLC