NEOpredict-Lung Data Support the Addition of Relatlimab to Preoperative Nivolumab in Resectable NSCLC

Administering the LAG-3–targeted antibody relatlimab (Opdualag) with nivolumab (Opdivo) prior to resection could offer additional clinical benefit for patients with PD-1–refractory, resectable non–small cell lung cancer (NSCLC), meriting further research on preoperative immune checkpoint inhibitor therapy (PICIT) in the neoadjuvant setting, according to Evan J. Lipson, MD.

This conclusion is supported by data from the phase 2 NEOpredict-Lung trial (NCT04205552), presented at the ESMO Congress 2022. Patients in both the nivolumab plus relatimab arm and single-agent nivolumab arm met the study’s primary endpoint of feasibility, which was defined as undergoing surgical resection within 43 days of initial PICIT administration. Secondary endpoints also indicated high efficacy and tolerability of this combination regimen, with an objective response rate of 27%, a complete or major pathologic response of 30%, and a 1-year overall survival rate of 100%.1 In the nivolumab-alone arm, these rates were 10%, 27%, and 92%, respectively.

The combination previously demonstrated efficacy in patients with melanoma. In the phase 2/3 RELATIVITY-047 trial (NCT03470922), first-line relatlimab plus nivolumab demonstrated a significant improvement in progression-free survival (PFS) for patients receiving the combination regimen vs those on single-agent immunotherapy. At a median follow-up of 19.3 months, the median PFS was 10.22 months and 4.63 months respectively (HR, 0.78; 95% CI, 0.64-0.94).²

“[NEOpredict-Lung provides us with] hypothesis-generating data that [can be used moving] forward to see if combination therapy might increase the number of complete pathologic responses or major pathologic responses [compared with] single-agent anti–PD-1 [therapy,” Lipson said in an interview with OncLive^® during the ESMO 2022 Congress.

In the interview, Lipson expanded on key takeaways from the NEOpredict-Lung trial, the additional benefit that PICIT may offer to patients who progress on other immunotherapies, and the effect that both NEOpredict-Lung and RELATIVITY-047 have on the role of immunotherapy in the lung and melanoma treatment paradigms.

Lipson is an associate professor at Kimball Institute for Cancer Immunotherapy, and a member of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland.

OncLive^®: What is the rationale for investigating relatlimab in combination with nivolumab for patients with NSCLC who progressed on previous immunotherapies?

Lipson: In the melanoma space, we've been testing relatlimab [alone] and in combination with nivolumab and some other agents for the better part of a decade. The first-in-human trial [of this combination demonstrated] that adding relatlimab to the treatment regimen of a patient who had progressed through anti–PD-1 monotherapy sometimes [produced improved] responses. That was true in NSCLC, melanoma and [several] other tumor types. [These findings] do seem [to indicate] that LAG-3 and PD-1 are non-redundant pathways, and that blocking them both [creates] some synergy.

Please provide more background on the NEOpredict-Lung trial.

[NEOpredict-Lung was] a small phase 2 study that looked at the use of relatlimab plus nivolumab vs nivolumab alone in patients with resectable NSCLC. The primary outcome of the study was whether patients made it to surgery, which is an important consideration. In the neoadjuvant space, drug regimens with a high toxicity profile [can potentially cause patients to] experience a toxicity and [not progress] to surgery. Conversely, if the efficacy of that regimen is not high enough, [the patient's] tumor could grow and [they could] miss a surgical window.

What should be noted regarding the trial design?

The dose of relatlimab used [in NEOpredict-Lung] was relatively low, similar to what was used in the melanoma space for the large phase 3 [RELATIVITY-047] study. However, relatlimab has been used in dose-escalation trials at much higher doses [than] the amount that was given in this study. Increasing the dose of relatlimab does seem to increase occupancy on peripheral CD8-positive T-cells.

As [Martin H. Schuler, MD, of the University Duisburg Essen] presented [at ESMO 2022], one amendment to [NEOpredict-Lung] is that they will increase the dose overlap of relatlimab to see if [there is] an increased signal.

What were the key study results?

The primary outcome of the study was whether patients [were able to undergo] surgical resection. As a first impression, it does seem like the study met its primary end point and both arms [progressed] to surgery. [Therefore,] nivolumab plus relatlimab seem to [have an] acceptable toxicity profile. Some of the secondary outcomes [that were] included [evaluated] what might have been driving [these complete or partial responses.] The investigators are excited about doing additional work [in this area.]

What are your hopes for how these results will affect the current treatment landscape?

The results from this study are hypothesis-generating. [They] suggest that adding additional immune checkpoint inhibitors targeting non-redundant immunoregulatory pathways [such as] PD-1, LAG-3 and CTLA-4 might change the treatment landscape in not only NSCLC, but other cancer types. Although the study itself is not practice changing, it lays the groundwork for larger trials [that will investigate whether] combining [multiple] agents blocks immune checkpoints in a combinatorial way, and [produces] synergistic antitumor activity.

How is the use of immunotherapy still being refined, as it relates to safety and efficacy?

One question that comes out of any neoadjuvant trial is whether [immunotherapy] is more effective in the neoadjuvant setting, the adjuvant setting, or both. There was a cooperative group trial reported here at [the ESMO 2022 Congress] looking at anti–PD-1 [therapy administered] in the neoadjuvant and adjuvant settings vs adjuvant setting only. We're excited to see whether the preclinical mouse models suggesting that neoadjuvant therapy might be more effective [are accurate] in human beings.

What other trials are exploring novel immunotherapies that you find intriguing?

We're excited to present our experience using anti–PD-1 in treatment-naïve patients with advanced basal cell carcinoma [BCC]. Historically, anti–PD-1 therapy has been tested in patients with advanced BCC only after they have received a hedgehog inhibitor, which is one standard of care. We [wanted to investigate if] the use of anti–PD-1 therapy in a treatment-naïve setting rather than a post-hedgehog inhibitor setting could be more effective.

In the study, we are giving nivolumab and relatlimab to patients who have progressive BCC [in order] to see if [administering] anti–LAG-3 [ alongside] anti–PD-1 [therapy] has a [positive] effect. Patients who progress on that therapy are then eligible to get ipilimumab (Yervoy) plus nivolumab. [Overall, this trial provides] a broad look at multi-therapy approaches for patients with advanced BCC.

References

1. Schuler MHH, Cuppens K, Ploenes T, et al. A randomized, multicentric phase II study of preoperative nivolumab plus relatlimab or nivolumab in patients with resectable non-small cell lung cancer (NEOpredict-Lung). Annal Oncol. 2022;33(suppl 7):LBA37. doi:10.1016/annonc/annonc1089
2. Long GV, Hodi FS, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in previously untreated metastatic or unresectable melanoma: Overall survival and response rates from RELATIVITY-047 (CA224-047). J Clin Oncol. 2022;40(suppl 36):360385-360385. doi:10.1200/jco.2022.40.36_suppl.360385