Not for everyone but will be of interest for some.....
LAG-3 (CD223)
Lymphocyte activation gene-3 (LAG-3, CD223) is a molecule that interacts with major histocompatibility complex (MHC) class II and is expressed by activated T cells, natural killers (NK) cells, B cells, and dendritic cells (DCs) [13,17]. Although the mechanism of action of LAG-3 is incompletely understood, its interaction with MHC class II causes downregulation of T cell cytokine production, CD4 and CD8 T cell expansion, and favors Treg phenotype adoption to prevent tissue damage and autoimmunity [17] T cells located in the TME, known as tumor-infiltrating lymphocytes (TILs), overexpress LAG-3 which results in cell dysfunction, immune exhaustion, and favorable conditions for tumor growth [18]. Thus, LAG-3 blockade favors immune activation against malignant cells, while enhancing the effect of other immune checkpoint inhibitors (ICIs) (e.g., anti-PD-1 agents) and possibly other forms of immunotherapy [17,19]. Combining LAG-3 inhibitors with other ICIs, however, could result in an increased incidence and severity of adverse events (AEs) [2]. Unfortunately, there are no biomarkers to predict who may benefit and who is likely to develop AEs from this therapy [19].
Six molecules are being investigated: five monoclonal antibodies (LAG525, REGN3767, BI 754111, tebotelimab, and FS118) and one LAG-3-Ig fusion protein (IMP321) as outlined below.
LAG525 (IMP701) is a monoclonal antibody (mAb) that targets LAG-3 and blocks the interaction with its ligand MHC class II. Preliminary data from a phase I/II clinical trial using LAG525 with or without spartalizumab in patients with advanced malignancies were published (NCT02460224) [20]. Out of 240 patients, 119 received LAG525 as monotherapy and 121 as combination therapy. Seventy-nine percent of patients receiving LAG525 monotherapy and 67% of patients on combination therapy discontinued therapy due to disease progression. Eleven of 121 patients in the combination group achieved a partial response (PR) and 1 patient had a complete response (CR). Data regarding response to monotherapy were not available [20]. Although the therapy was well tolerated, dose-limiting toxicities (DLTs) occurred in 4 patients in each arm and included grade 3 and 4 pneumonitis, acute kidney injury, and autoimmune hepatitis [20]. This trial has completed recruitment, and final data analysis is ongoing. Preliminary results of combination therapy revealed a 10% overall response rate (ORR [CR + PR]). However, it remains unclear whether this response was due to spartalizumab, LAG525, or both. This should be clarified once the finalized data are published. It would also be important to determine the efficacy of spartalizumab monotherapy in this setting.
Another phase II clinical trial investigated combination therapy with LAG525 and spartalizumab in patients with relapsed and/or refractory advanced solid or hematologic malignancies (NCT03365791) [21]. At the time of publication, 76 patients had been recruited, but only 72 were eligible for analysis. The primary endpoint was disease control rate (DCR [CR + PR + stable disease]). Preliminary results revealed a DCR that was particularly encouraging for neuroendocrine tumors (86%), diffuse large B cell lymphoma (43%), and small cell lung cancer (27%) [21]. The gastroesophageal cancer cohort was terminated because it did not reach the threshold for clinical benefit and was deemed futile [21]. No DLTs were mentioned. AEs affected 57% of all patients. Only 11/72 patients had grade 3 or 4 AEs including dyspnea, fatigue, and poor appetite [21]. This trial was completed, and final analysis is pending. Preliminary results suggest that LAG525 with spartalizumab may be effective for some but not all malignancies. Further research to identify patients who will benefit the most is warranted. In addition, it is important to determine whether the DCR seen was due to LAG525, spartalizumab, or combination therapy.
REGN3767 (R3767) is another mAb that targets LAG-3, blocking its interaction with MHC class II. A first-in-human phase I clinical trial using RGN3767 alone or in combination with cemiplimab in patients with advanced solid and hematologic malignancies who had progressed on prior lines of therapy is ongoing (NCT03005782). A total of 67 patients (25 in the monotherapy cohort and 42 in the combination group) with a median age 60–66 years were included [22]. In the monotherapy group, the ORR was 0% and the DCR was 48%. There were no CR/PR and 12 patients achieved stable disease (SD). The ORR in the combination group was 5% and the DCR was 31%. Two patients achieved PR and 11 had SD [22]. There were 12 patients that crossed over from monotherapy to the combination arm. Two of these achieved PR and 6 SD. Overall, the drug was well tolerated with only 1 DLT in the combination group consisting of a grade 4 elevation of creatinine kinase associated with a grade 3 myasthenic syndrome and a grade 1 elevation of troponin. In addition, there was 1 case of grade 3 hypothyroidism in the combination group and 2 cases of grade 3 elevation of AST and ALT in the monotherapy group. The most common AEs were mild and included nausea in the monotherapy group and fatigue in the combination group [22]. Currently, the trial is still open and actively recruiting. Based on the available results, it appears that combination therapy with REGN3767 is more effective than monotherapy. Combination therapy, however, is more likely to result in severe toxicities. Future research should clarify which immunotherapy agent (cemiplimab or other) is best when combined with REGN3767.
BI 754091, another anti-LAG-3 mAb, is being tested in combination with anti-PD-1 therapy in three separate phase I clinical trials (NCT03156114,NCT03433898,NCT03780725) and one phase II clinical trial (NCT03697304). A review of the data from these trials was published and included here [23]. There were 321 patients with advanced or metastatic solid tumors included. The median age of patients was 63, and 62% (n = 200) were males. Although there is no mention of efficacy or clinical response, this medication showed an overall acceptable safety profile and was deemed similar to other ICIs. There were 21 cases of DLTs, particularly infusion-related reactions (n = 6). Serious AEs occurred in 77 patients (27%) including pleural effusion (n = 6), deep venous thrombosis (n = 4), cardiac tamponade (n = 1), and acute kidney injury (n = 1). Eighty-eight patients (30.9%) had grade 3 or 4 toxicities consisting of fatigue or immune-related AEs (irAEs). Although 86.7% experienced any AE, most were grade 1 and 2 and included fatigue (22.8%), fever (18.6%), or nausea [23]. The phase I trials are not actively recruiting patients. The phase II trial, however, is actively recruiting. While no efficacy data is available, results of these trials will help elucidate the role of anti-LAG3 therapy in combination with existing targets (anti-PD1 therapy). In addition, it will provide information regarding which combination strategy is most effective.
Tebotelimab (MGD013), a bi-specific mAb targeting both LAG-3 and PD-1, has been studied in a phase I clinical trialNCT03219268. This drug was used alone or in combination with margetuximab (for patients who had expression of HER2 on their tumors) in 207 patients with advanced or metastatic solid or hematologic malignancies [24]. Fifty of these patients were part of the dose-escalation cohort; 157 were included in the expansion cohort. Among the dose-escalation group, only 29 patients were response-evaluable. The ORR in this group was 10%, and DCR was 55% with 3 patients achieving a confirmed PR, 1 unconfirmed PR, and 13 SD [24]. In the expansion cohort, 41 patients were response-evaluable. The ORR in this group was 7% and DCR 59% with 3 cases of PR, and 21 with SD. Among 6 response-evaluable patients with HER2 expression who received margetuximab, 3 had PR [2 breast cancer (BC), 1 colorectal cancer (CRC)], and 2 SD [24]. There were 2 cases of DLTs including immune-mediated hepatitis and increased levels of lipase. AEs were reported in 146 patients (70.5%), but only 23.2% were grade ≥ 3 including rash, pancreatitis, and colitis. Most common grade 1–2 AEs were fatigue (19%) and nausea (11%) [24]. This trial is currently open for enrollment. Patients appear to respond to monotherapy with tebotelimab. This investigational drug will likely advance to subsequent phases of clinical trial. Five out of 6 HER2 positive patients had response. While the sample size was small, it raises the question of whether HER2 positivity might increase response to anti-LAG-3 therapy. It is also possible that the response seen was due to the anti-HER2 therapy.
FS118, a bi-specific antibody that targets LAG-3 and PD-L1, is being studied in a first-in-human phase I clinical trial in patients with advanced or metastatic solid malignancies who have failed prior anti-PD-1/PD-L1 therapy (NCT03440437). Recruitment was completed, but no results have been published to date. While no efficacy data are available, results of this trial will be important to help define the role anti-LAG-3 therapy when rechallenging patients who failed previous anti-PD-1/PD-L1 therapy.
Eftilagimod alpha (IMP321) is a soluble recombinant fusion protein that binds directly to MHC class II and blocks the interaction with LAG-3 on T cells. This molecule was tested in conjunction with pembrolizumab in 18 patients with advanced melanoma in a phase I clinical trial (NCT02676869) [25]. Fifty percent of patients showed a tumor reduction, but no specifics were provided. Of these, one patient achieved CR [25]. There were no DLTs reported nor were there any grade ≥ 4 toxicities. This trial is currently closed, and data analysis is ongoing. Those eligible for enrollment were actively receiving treatment with pembrolizumab and had not achieved a CR. The results will help assess the added benefit of anti-LAG-3 therapy in those patients with suboptimal response to anti-PD-1 therapy.
In another phase I clinical trial, subcutaneous eftilagimod alpha (IMP321) was combined with intravenous avelumab in 8 patients with advanced solid malignancies (NCT03252938) [26]. Preliminary results in 6 evaluable patients out of 8 patients demonstrated an ORR of 17% and DCR of 33% with 1 PR, 1 SD, and 4 progressive disease (PD). Overall, the therapy was well tolerated without DLTs. There was one grade 5 AE (acute kidney injury), no grade 4 AEs, and twelve grade 3 AEs, none of which were attributed to the study drug. Most AEs were grade 1 and 2 and included nausea, pain, and injection site reaction [26]. This trial is still active but is not currently recruiting. Final results will be important to assess the role of anti-PD-L1 therapy in combination with anti-LAG-3 therapy. In addition, it will help clarify which combination therapy is better tolerated and most effective. Of note, this trial will also assess for the safety of intratumoral and intraperitoneal use of eftilagimod alpha (IMP321) (NCT03252938).
Finally, a phase II clinical trial using eftilagimod alpha (IMP321) with pembrolizumab is also being performed in patients with advanced or metastatic non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) (NCT03625323). Preliminary results of 48 patients (73% males) with a median age of 66 years were published [27]. Among 17 patients with NSCLC who received eftilagimod alpha (IMP321) as first line, the ORR was 47% and DCR was 82% with 8 PR and 6 SD. Additionally, 6/15 patients (40%) with HNSCC who received eftilagimod alpha (IMP321) as second line and who had not received PD-1/PD-L1 therapy also achieved a PR [27]. The therapy was well tolerated, and only 3 patients discontinued treatment due to AEs. The most common toxicities included cough (31%), fatigue (19%), and diarrhea (15%) [27]. This trial is active and recruiting patients. While the sample size was limited, the clinical response to therapy appeared promising. The conclusion of this trial will help determine the added benefit of upfront anti-LAG-3 therapy to anti-PD-1 therapy. In addition, subset analysis may help define the role of anti-LAG-3 therapy in those patients previously treated with anti-PD-1/anti-PD-L1 agents.
this is an extract from a broader report issued March 2021...
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