Lagging ahead: LAG-3 checkpoint inhibition for advanced melanoma
By Warren R. Heymann, MD, FAAD
May 11, 2022
Vol. 4, No. 19
Checkpoint inhibition has revolutionized the treatment of advanced melanoma over the past decade, beginning with the release of the anti-CTLA4 checkpoint inhibitor ipilimumab (Yervoy). This was followed by the development of the anti-PD-1 inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo), and combination therapies of anti-CTLA4 and anti-PD1 checkpoint inhibition. Although nivolumab plus ipilimumab is now the standard of care for patients with advanced melanoma, approximately 30% of patients still receive PD1 monotherapy to avoid toxicity concerns. (1) As adjuvant therapy in high-risk resected stage III or IV melanoma, PD-1 inhibitors’ durable cancer control approaches nearly 50% of patients. (2)
This commentary will focus on the newest checkpoint inhibitors against lymphocyte activation gene 3.
According to Lythgoe et al: “Lymphocyte-activation gene 3 (LAG-3) is a coreceptor found on activated T-lymphocytes, activated B-lymphocytes, and natural killer (NK) cells. It is closely related to CD4 where it shares multiple common and divergent features. It contains specific binding sites with high affinity to major histocompatibility complex (MHC) Class II and functions as an inhibitor of T-cell signalling. Tumour-infiltrating lymphocytes with high LAG-3 expression have been found in many solid tumours including ovarian cancer, melanoma, colorectal cancer and haematological malignancies including Hodgkin and diffuse large B-cell lymphoma. LAG-3 antagonism has been demonstrated to restore the anti-tumourigenic function of T-cells in vivo, however, mechanistic knowledge remains relatively poorly defined.” (3) Two types of LAG3‐targeting agents being used as antitumor immunotherapies include a LAG3 soluble dimeric recombinant protein (IMP321) and LAG-3 monoclonal antibody (mAb). IMP321 acts as an antigen‐presenting cell activator to exert an antitumor effect. (4) IMP321 has shown preliminary efficacy as a melanoma vaccine. (5) LAG-3 mAb blocks the binding of LAG-3 and its ligands to improve the antitumor activity of the host. Many IMP321 and LAG3 mAb‐related clinical trials for various malignancies are ongoing, most of which are combined with anti‐PD1 therapy. LAG3 and PD1 / PDL1 / CTLA4 bispecific antibody immunotherapy studies are also underway. (4)
Tawbi et al, in a study funded by Bristol Myers Squibb, performed a phase 2-3, global, double-blind, randomized trial of the LAG-3 blocking antibody relatlimab and nivolumab as a fixed-dose combination compared to nivolumab alone when administered intravenously every 4 weeks to patients with previously untreated metastatic or unresectable melanoma. The primary endpoint was progression-free survival as assessed by a blinded independent central review. The median progression-free survival was 10.1 months with relatlimab-nivolumab as compared with 4.6 months with nivolumab (hazard ratio for progression or death, 0.75 P = 0.006 by the log-rank test). Progression-free survival at 12 months was 47.7% with relatlimab-nivolumab as compared with 36.0% with nivolumab. Progression-free survival across key subgroups favored relatlimab-nivolumab over nivolumab. The benefit of treatment with relatlimib-nivolumab was observed regardless of patients’ BRAF mutation status. Grade 3 or 4 treatment related adverse were higher in patients with relatlimab-nivolumab group compared to nivolumab group alone (18.9% vs 9.7%), the most common being hypothyroidism or thyroiditis (18% of patients), “rash” (9.3%), and diarrhea or colitis (6.8%). The authors concluded: “The inhibition of two immune checkpoints, LAG-3 and PD-1, provided a greater benefit with regard to progression-free survival than inhibition of PD-1 alone in patients with previously untreated metastatic or unresectable melanoma.” (6) (I have no conflict of interest, financial or otherwise, with Bristol Myers Squibb).
In an editorial accompanying the manuscript by Tawbi et al, Frampton and Sivakumar note that further studies will determine how the survival benefit of relatlimab-nivolumab compares to nivolumab-ipilimumab. With longer follow-up and the development of new biomarkers, differences in survival between those with high versus low LAG-3 expression should be determined. Additionally, it will be valuable to determine if relatlimab is useful as salvage therapy should primary immune checkpoint therapy fail, or if it is beneficial in combination with, or after, targeted therapy aimed at BRAF and MEK. (7)
To date, various dermatologic adverse reactions have been reported with the checkpoint inhibitors, notably pruritus, morbilliform eruptions, and vitiligo. Lichenoid eruptions are common (possibly more so histologically than clinically), and blistering eruptions (predominantly bullous pemphigoid) are increasingly reported. Fortunately for the vast majority of patients, these respond to therapy, and the anti-neoplastic therapy may be continued. (8) I anticipate similar reports to be forthcoming with LAG-3 inhibitors.
In conclusion, LAG-3 checkpoint inhibition is on the horizon. Further studies combined with other checkpoint or targeted therapies to determine its precise role in the treatment of melanoma (and other cancers) will not be lagging.
Point to Remember: Lymphocyte-activation gene 3 (LAG-3) inhibition by relatlimab is the newest checkpoint inhibitor that has demonstrated efficacy in advanced melanoma when used in combination with nivolumab. Studies are ongoing to determine the proper role for this (and other) LAG-3 checkpoint inhibitors for melanoma and other malignancies.
Our expert’s viewpoint
Jamin C. Morrison, MD
Medical Director, Division of Hematology/Medical Oncology, Cooper University Health Care
Assistant Professor of Medicine, Cooper Medical School of Rowan University
The modern era of immunotherapy began in 2011 with the approval of ipilimumab, a CTLA-4 checkpoint inhibitor, and was followed swiftly by the integration of both CTLA-4 and PD-1/PDL-1 checkpoint blockade into standard practice for advanced melanoma, among a wide variety of other malignancies. This revolution, primarily in the use of PD-1/PD-L1 drugs nivolumab and pembrolizumab, has driven a vast improvement in disease control and long-term survival, as compared to prior decades. Furthermore, we’ve continued to see checkpoint inhibitor therapy deployed in earlier stages, including node-positive (stage III) disease as well as most recently the approval of pembrolizumab for node-negative deep lesions (stage IIB and IIC). The approval of relatlimab, a novel anti-LAG-3 monoclonal antibody, provides an exciting new therapeutic approach to the management of advanced melanoma. Data from the RELATIVITY-047 study demonstrate that relatlimab given in combination with nivolumab resulted in a longer progression-free survival (10.1 months versus 4.6 months) as compared to nivolumab monotherapy in untreated patients with advanced or unresectable melanoma. The data furthermore suggest that the toxicity profile is in large part not substantially worse than single-agent and may be considerably milder than the PD-1+CTLA-4 combination (nivolumab + ipilimumab). (6) Interestingly, the FDA approval for the combination of relatlimab + nivolumab allowed a far broader indication, for any patient with metastatic or unresectable disease, irrespective of prior lines of therapy. This raises the question about the appropriate place for this novel therapeutic agent in the course of treatment of patients with advanced melanoma. We eagerly await additional data from related studies evaluating the role of relatlimab + nivolumab after progression on single-agent therapy, or after progression on nivolumab + ipilimumab doublet therapy. We furthermore await guidance on therapeutic sequencing of BRAF targeted therapy for those patients with actionable BRAF mutations. Finally, in patients with CNS metastases, the combination of nivolumab + ipilimumab has been considered the most effective systemic therapy and we eagerly await clarification on CNS efficacy of this novel combination, relatlimab + nivolumab. This recent approval is, in summary, an exciting and eagerly anticipated development in the treatment of patients with advanced melanoma and we await additional data to help guide the implementation of therapy.
Mullard A. LAG3 pushes immuno-oncology's leading edge. Nat Rev Drug Discov. 2022 Mar;21(3):167-169. doi: 10.1038/d41573-022-00036-y. PMID: 35177834.
Carlino MS, Larkin J, Long GV. Immune checkpoint inhibitors in melanoma. Lancet. 2021 Sep 11;398(10304):1002-1014. doi: 10.1016/S0140-6736(21)01206-X. PMID: 34509219.
Lythgoe MP, Liu DSK, Annels NE, Krell J, Frampton AE. Gene of the month: lymphocyte-activation gene 3 (LAG-3). J Clin Pathol. 2021 Sep;74(9):543-547. doi: 10.1136/jclinpath-2021-207517. Epub 2021 Jun 28. PMID: 34183437.
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Legat A, Maby-El Hajjami H, Baumgaertner P, Cagnon L, Abed Maillard S, Geldhof C, Iancu EM, Lebon L, Guillaume P, Dojcinovic D, Michielin O, Romano E, Berthod G, Rimoldi D, Triebel F, Luescher I, Rufer N, Speiser DE. Vaccination with LAG-3Ig (IMP321) and Peptides Induces Specific CD4 and CD8 T-Cell Responses in Metastatic Melanoma Patients--Report of a Phase I/IIa Clinical Trial. Clin Cancer Res. 2016 Mar 15;22(6):1330-40. doi: 10.1158/1078-0432.CCR-15-1212. Epub 2015 Oct 23. PMID: 26500235.
Tawbi HA, Schadendorf D, Lipson EJ, Ascierto PA, Matamala L, Castillo Gutiérrez E, Rutkowski P, Gogas HJ, Lao CD, De Menezes JJ, Dalle S, Arance A, Grob JJ, Srivastava S, Abaskharoun M, Hamilton M, Keidel S, Simonsen KL, Sobiesk AM, Li B, Hodi FS, Long GV; RELATIVITY-047 Investigators. Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med. 2022 Jan 6;386(1):24-34. doi: 10.1056/NEJMoa2109970. PMID: 34986285.
Frampton AE, Sivakumar S. A New Combination Immunotherapy in Advanced Melanoma. N Engl J Med. 2022 Jan 6;386(1):91-92. doi: 10.1056/NEJMe2116892. PMID: 34986291.
Heymann WR. Checking in on the adverse reactions to checkpoint inhibitors. Dermatology World Insights and Inquiries, Oct 17, 2016. https://www.aad.org/dw/dw-insights-and-inquiries/dermatopathology/checking-in-on-the-adverse-reactions-to-checkpoint-inhibitors.
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