A phase 2, multicenter, open-label study of anti-LAG-3 ieramilimab in combination with anti-PD-1 spartalizumab in patients with advanced solid malignancies

Our plain-English summary of A phase 2, multicenter, open-label study of anti-LAG-3 ieramilimab in combination with anti-PD-1 spartalizumab in patients with advanced solid malignancies, by C.C. Lin, E. Garralda, P. Schöffski, et al (Oncoimmunology, 2024).

The study

• Authors: C.C. Lin, E. Garralda, P. Schöffski, D.S. Hong, L.L. Siu, M. Martin, M. Maur, R. Hui, R.A. Soo, J. Chiu, T. Zhang, B. Ma, C. Kyi, D.S. Tan, P.A. Cassier, J. Sarantopoulos, A. Weickhardt, R.D. Carvajal, J. Spratlin, T. Esaki, F. Rolland, W. Akerley, B. Deschler-Baier, L. Rispoli, T.S. Samant, N.R. Chowdhury, D. Gusenleitner, E.L. Kwak, V. Askoxylakis, F. De Braud
• Journal: Oncoimmunology
• Published: 2024;13(1):2290787
• Cited by: 34 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Ieramilimab, a humanized anti-LAG-3 monoclonal antibody, was well tolerated in combination with the anti-PD-1 antibody spartalizumab in a phase 1 study. This phase 2 study aimed to further investigate the efficacy and safety of combination treatment in patients with selected advanced (locally advanced or metastatic) solid malignancies. Eligible patients with non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma (RCC), mesothelioma, and triple-negative breast cancer (TNBC) were grouped depending on prior anti-PD-1/L1 therapy (anti-PD-1/L1 naive or anti-PD-1/L1 pretreated). Patients received ieramilimab (400 mg) followed by spartalizumab (300 mg) every 3 weeks. The primary endpoint was objective response rate (ORR), along with safety, pharmacokinetics, and biomarker assessments. Of 235 patients, 142 were naive to anti-PD-1/L1 and 93 were pretreated with anti-PD-1/L1 antibodies. Durable responses (>24 months) were seen across all indications for patients naive to anti-PD-1/L1 and in melanoma and RCC patients pretreated with anti-PD1/L1. The most frequent study drug-related AEs were pruritus (15.5%), fatigue (10.6%), and rash (10.6%) in patients naive to anti-PD-1/L1 and fatigue (18.3%), rash (14.0%), and nausea (10.8%) in anti-PD-1/L1 pretreated patients. Biomarker assessment indicated higher expression of T-cell-inflamed gene signature at baseline among responding patients. Response to treatment was durable (>24 months) in some patients across all enrolled indications, and safety findings were in accordance with previous and current studies exploring LAG-3/PD-1 blockade.

© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.

In plain English

This phase 2 part of an open-label, multicenter trial without a comparison group tested ieramilimab (blocking LAG-3) plus spartalizumab (blocking PD-1). Most patients received both every 3 weeks; 21 with triple-negative breast cancer received them every 4 weeks at higher doses. From August 2017 to December 2020, 235 patients with advanced cancers enrolled in 12 countries. Of these, 57 had mesothelioma (pleural or peritoneal not stated), and the others had non-small cell lung cancer, melanoma, renal cell carcinoma or triple-negative breast cancer. Asbestos was not discussed. Of 41 mesothelioma patients not previously given PD-1/PD-L1 drugs, 7 (17.1%; 90% confidence interval 8.3 to 29.7%) had an objective response (two complete, five partial). Of 16 previously treated, 1 (6.3%; 90% confidence interval 0.3 to 26.4%) had a partial response. Median time without disease worsening in these groups was 5.5 and 3.4 months. Across all cancers, suspected drug-related side effects affected 66.2% of 142 patients not previously given these drugs and 63.4% of 93 previously treated. The authors concluded the combination was associated with clinical activity across cancer types. They noted small groups, mixed tumor subtypes and no comparison arms.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Phase 2 part of a phase 1/2 multicenter, open-label, international, non-randomized drug trial
• Who was studied: 235 patients with advanced (locally advanced or metastatic) solid tumors: mesothelioma (n = 57), NSCLC (n = 42), melanoma (n = 42), renal cell carcinoma (n = 38), and triple-negative breast cancer (n = 56). They were enrolled August 2017 to December 2020 at 25 sites in 12 countries. 142 (60.4%) had not received PD-1/L1 inhibitors and 93 (39.6%) had. The mesothelioma groups were 41 untreated and 16 pretreated with these drugs.
• Exposure: No asbestos or fiber exposure was studied. The exposure was treatment with ieramilimab 400 mg followed by spartalizumab 300 mg by intravenous infusion every 3 weeks. An alternative schedule of ieramilimab 600 mg plus spartalizumab 400 mg every 4 weeks was used in 21 anti-PD-1/L1-naive triple-negative breast cancer patients.
• Main results:
  • Mesothelioma patients not previously treated with anti-PD-1/L1 drugs (n = 41): objective response rate 17.1% (7 patients; 90% CI 8.3 to 29.7%), with two complete and five partial responses.
  • Mesothelioma patients previously treated with anti-PD-1/L1 drugs (n = 16): objective response rate 6.3% (one partial response; 90% CI 0.3 to 26.4%).
  • Median progression-free survival in mesothelioma by RECIST v1.1/irRC was 5.5/5.6 months for patients not previously treated with anti-PD-1/L1 drugs.
  • Median progression-free survival in mesothelioma by RECIST v1.1/irRC was 3.4/3.4 months for patients previously treated with anti-PD-1/L1 drugs.
  • Responses lasting more than 24 months were seen in every cancer type among patients not previously treated with anti-PD-1/L1 drugs.
  • The highest response rate was 26.3% (five partial responses; 90% CI 11.0 to 47.6%), in renal cell carcinoma patients not previously treated with anti-PD-1/L1 drugs.
  • Adverse events suspected to be drug-related occurred in 66.2% of the 142 patients not previously treated with anti-PD-1/L1 drugs and in 63.4% of the 93 pretreated patients, across all cancer types.
  • The most frequent suspected drug-related adverse events in patients not previously treated with anti-PD-1/L1 drugs were pruritus (15.5%), fatigue (10.6%) and rash (10.6%).
  • Serious adverse events suspected to be treatment-related occurred in 8.5% of the untreated group and 2.2% of the pretreated group.
  • Across all cancer types combined, responding patients had higher baseline expression of a T-cell-inflamed gene signature. By individual cancer type, this reached statistical significance only in melanoma.
  • LAG-3 measured by immunohistochemistry in 219 baseline samples did not correlate with response.
• The authors' conclusion: The authors concluded that combined LAG-3 and PD-1 blockade with ieramilimab and spartalizumab was associated with clinical activity across different cancer types. They said their results support further exploration in selected patient populations.
• Limitations the authors state:
  • Relatively small numbers of patients in each group, and tumor subtype heterogeneity within each cancer type.
  • No comparator arms in a non-randomized design. The authors said randomized trials against spartalizumab alone are needed to clarify the contribution of LAG-3 blockade.
  • Enrolled patients had received previous standard therapy, often multiple prior lines, which likely limited the trial's ability to show improved efficacy.
  • Tumors were not prospectively selected for PD-L1 status.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer.

Medical terms in this study, explained in our Lexicon: Monoclonal Antibody, Non-Small Cell Lung Cancer, Carcinoma, Mesothelioma, Biomarker.

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