Novel Immunotherapy Combos Target TIM-3 and PD-1/PD-L1 Networks

Fred R. Hirsch, MD, PhD

The immune checkpoint TIM-3 is shaping up to be a viable target for designing therapies for patients with non–small cell lung cancer (NSCLC) and other malignancies, according to a growing body of early scientific and clinical data. Investigative efforts so far are focusing on pairing novel agents directed at TIM-3 activity with PD-1/PD-L1 immune checkpoint inhibitor (ICI) therapy.^1,2

The research involving TIM-3 comes amid continuing efforts to boost the efficacy of ICI immunotherapy. Although PD-1/PD-L1 ICIs have improved outcomes for patients in a range of tumor types, primary and acquired resistance represents a significant unmet need. Investigators are exploring ICI combinations, including regimens involving novel immune checkpoints such as TIM-3, as a means of increasing response rates.^3,4

The potential for leveraging TIM-3 for anticancer therapy is being tested in early studies in several solid malignancies, with many of the trials exploring dual combination of ICIs aimed at TIM-3 and PD-1/PD-L1 immune checkpoints. Other approaches include bispecific antibodies that simultaneously target TIM-3 and PD-1.

In NSCLC, TIM-3 is among the intriguing emerging targets in development, accord-ing to experts who participated in Molecular Targets on the Horizon in Non–Small Cell Lung Cancer OncLive^® Scientific Interchange & Workshop, a panel discussion held on September 27.

“The theory here is that you can overcome I/O [immuno-oncology] resistance with a combination of a TIM-3 antibody with a PD-1/PD-L1 antibody,” Fred R. Hirsch, MD, PhD, said during the program. “We don’t have advanced clinical data…but I think we will see more and more of this target in the future.”

Hirsch, a longtime biomarker expert in the lung cancer field, is executive director at the Center for Thoracic Oncology in The Tisch Cancer Institute at Mount Sinai and the Joe Lowe and Louis Price Professor of Medicine (Hematology and Medical Oncology) at Icahn School of Medicine at Mount Sinai, both in New York, New York.

Prognostic Implications of TIM-3 Expression

TIM-3, which stands for T-cell immunoglobulin and mucin domain 3, is a member of a family of coinhibitory receptors that help regulate immune responses. First described in 2002, TIM-3 is a cell-surface glycoprotein that can be expressed both on tumor cells and multi-ple types of immune cells.^2,4-6 Hirsch noted that TIM-3 particularly is expressed on CD4-positive and CD8-positive T cells and often is coexpressed with other immune checkpoints such as PD-1 and TIGIT.

Investigators have identified 4 ligands that interact with TIM3: galectin-9, phos-phatidylserine, HMGB1, and CEACAM1.⁶ Galectin-9 is considered TIM-3’s main ligand⁶; binding of TIM-3 with this ligand inhibits an immune response by promoting cell death in TIM3-expressing T cells.² TIM-3 also is upregulated on regulatory T cells, which hampers effector T cell functions. Specifically, TIM-3 overexpression contributes to T-cell exhaustion, which is characterized by a loss of T-cell effector functions, expression of inhibitory receptors, and alterations in transcriptional functions.²

Hirsch noted that TIM-3 expression has a “complex biology” that negatively affects the immune system. “It is demonstrated preclinically that TIM-3 expression leads to dysfunctional lymphocytes and a dysfunc-tional immune reaction,” he said.

Findings from a meta-analysis published in Frontiers in Oncology⁷ in August 2020 illustrate the prognostic impact of TIM-3 expression, according to Hirsch. “TIM-3 protein expression is related to poor over-all survival, poor outcomes, and increased capacity of metastasis,” he said. “And that is certainly a bad prognostic indicator.”

The meta-analysis was based on findings involving 3072 patients with solid tumors who were treated during 21 studies reporting results from 2012 to 2019 from China, Japan, Korea, and Poland. Thirteen tumor types were represented in the study populations. TIM-3 protein expression was evaluated via immunohistochemistry (IHC) on tumor cells and/or tumor-infiltrating lymphocytes (TILs).

For the entire study population, TIM-3 overexpression correlated with poor overall survival (HR, 1.73; 95% CI, 1.39-2.15; P < .001). Additionally, TIM-3 expression was associated with positive lymph node metastases (N+ vs N–; OR, 1.59; P = .013), higher tumor grade (G2-3 vs G1; OR, 1.68; P = .002), and PD-L1 expression (PD-L1 high vs PD-L1 low; OR, 3.26; P < .001).⁷

In terms of tumor types, elevated TIM-3 protein expression was a negative predictor of overall survival (OS) for patients with NSCLC, gastric cancer, esophageal squamous cell carcinoma, and other cancers but not for participants with breast cancer. In a further analysis, investigators analyzed data on TIM-3 mRNA expression for patients with NSCLC, gastric cancer, and breast cancer from a public database and found that the results aligned with their findings on the prognostic impact based on protein expression. High TIM-3 mRNA expression was significantly correlated with poor OS outcomes in patients with NSCLC (HR, 1.46; P < .001) and gastric cancer (HR, 1.41; P = .0038) but not breast cancer (HR, 0.79; P = .51).⁷

Investigators also examined the impact of TIM-3 protein expression on disease-free survival (DFS) outcomes based on findings from 7 studies involving 1243 patients. For the overall population, the data showed that TIM-3 expression did not correlate with DFS (HR, 1.39; 95% CI, 0.75-2.57; P = .297). However, elevated TIM-3 expression was significantly associated with shorter DFS in patients with NSCLC (HR, 2.40; P < .001).

Another study finding showed a differ-ence in the impact of TIM-3 expression on tumor cells vs TILs. TIM-3 overexpression was significantly associated with worse OS outcomes on tumor cells (HR, 2.10; P < .001) compared with TILs (HR, 1.34; P = .105).

Investigators noted that TIM-3 expression on tumor cells appears to have greater prognostic value than levels on TILs but that further research is needed to verify this signal. The authors also said that because most of the participants whose data were examined live in East Asia, similar analyses should be conducted on results from European patients. Another limitation involved the calculation of TIM-3 IHC expression; the antibodies and cut-off values differed among studies included in the meta-analysis.⁷

Dual Blockade Strategies

In 2010, investigators established the negative impact on the immune system of upregulated TIM-3 and PD-L1 coexpression on melanoma specimens and suggested that a combination blockade strategy would be effective.⁸ Both TIM-3 and PD-L1 overexpression are markers of T-cell exhaustion; inhibiting both may result in a restoration of T-cell proliferation and cytokine production, thus generating an immune response.²

Results of in vitro studies show that combining TIM-3 inhibition with a PD-1/ PD-L1 antibody increases production of interferon γ.^2,9 “If you combined a blockade of TIM-3, which is the same mechanism as with PD-1/PD-L1, you actually see quite a lot of synergy,” Hirsch said. “…You see improvement of lymphocyte function and penetration and immune capacity.”

Early data from several clinical trials are encouraging, investigators say. In 2018, investigators reported the first findings from combination therapy with a TIM-3directed antibody and a PD-1 ICI, cobolimab (TSR-022) and dostarlimab-gxly (Jemperli), respectively, for patients with NSCLC who participated in the first-in-human multicohort phase 1 AMBER study (NCT02817633).¹⁰

At the time of data cutoff, 39 patients with NSCLC whose disease had progressed after anti–PD-1 therapy had received cobolimab at either 100 mg or 300 mg plus a fixed dose of dostarlimab at 500 mg. Of the 14 patients who received the lower dose of cobolimab, 11 were evaluable for response; 1 had a confirmed partial response by immune-related RECIST criteria and 3 had stable disease. Of the 25 patients who received the higher dose of cobolimab, 20 were evaluable for response; 3 had confirmed partial responses and 8 had stable disease. All objective responses were among patients with PD-L1 tumor proportion scores of 1% or more.

Overall, the AMBER study, which seeks to enroll 369 participants, includes 2 parts. Part 1 comprises 8 experimental arms evaluating cobolimab as monotherapy and in combination with dostarlimab, the PD-1 inhibitor nivolumab (Opdivo), the antiLAG-3 antibody TSR-033, or chemotherapy in patients with advanced solid tumors. In part 2, there are separate cohorts testing cobolimab as monotherapy or in combination with dostarlimab in patients with NSCLC, melanoma, and colorectal cancer.

Investigators said the combination regimen was well tolerated across multiple dosing levels and that the responses showed the strategy is worth pursuing.¹¹ However, they recommended increasing the dose of cobolimab to 900 mg for the NSCLC expansion cohort after analysis demonstrated that the 300-mg dose was inadequate for maintaining a maximal pharmacodynamic effect.¹⁰

Meanwhile, triplet therapy with cobolimab plus dostarlimab and docetaxel is being evaluated in patients with advanced NSCLC in the phase 2/3 COSTAR Lung study (NCT04655976). Another experimental cohort is testing dostarlimab plus docetaxel, and the comparator arm is evaluating docetaxel monotherapy.

As these trials continue, dostarlimab has moved into the ranks of approved therapies. In separate decisions in 2021, the FDA granted dostarlimab accelerated approvals for adult patients with mismatch repair– deficient recurrent/advanced solid tumors or endometrial cancer that has progressed on or following prior treatment who have no satisfactory alternative treatment options.¹²

In other early findings, investigators reported that the combination of sabatolimab (MBG453), a TIM-3 antibody, and spartalizumab (PDR001), a PD-1 ICI, generated partial responses lasting between 12 and 27 months among 6% of 86 patients with advanced solid tumors who received the regimen in an ongoing phase 1/2 study (NCT02608268). The responders included 2 patients with colorectal cancer and 1 each with NSCLC, malignant perianal melanoma, and small cell lung cancer. No responses were observed with sabatolimab monotherapy. The most common treatment-related adverse effect was fatigue, which was reported in 9% of those who received monotherapy and in 15% who had the combination.¹³

Another experimental TIM-3 antibody, LY3321367, was tested as monotherapy and in combination with LY3300054, a PD-L1 inhibitor, in patients with advanced cancers during a phase 1 study (NCT03099109). In April 2021, investigators reported that the agent had an acceptable safety profile but exhibited “only modest antitumor activity.” In the NSCLC monotherapy expansion cohort, the objective response rate (ORR) was 0% among 23 patients who were refractory to PD-1/PD-L1 therapy and 7% among 14 prior ICI responders. In the combination expansion cohorts, the ORR was 4%.¹⁴ The study is active but no longer recruiting participants, according to ClinicalTrials.gov.

BGB-A425 Plus Tislelizumab

From the roster of novel regimens in development, Hirsch highlighted an ongoing phase 1/2 study (NCT03744468) testing the novel TIM-3 antibody BGB-A425 in combination with tislelizumab, a PD-1 inhibitor.

In the phase 1 dose-escalation phase, patients with locally advanced or metastatic unresectable solid tumors will receive BGB-A425 IV at increasing dosing levels ranging from 2 mg to 800 mg plus tislelizumab at 200 mg IV. The primary end points are safety, tolerability, and the identification of the recommended phase 2 dose.

In the phase 2 stage, the combination will be tested in separate cohorts of patients with recurrent or metastatic head and neck squamous cell carcinoma, extensive-stage NSCLC, or advanced gastric/gastroesophageal junction cancer. The primary end point is the objective response rate.⁹

Investigators are seeking to recruit up to 42 patients from Australia and the United States to participate in phase 1 of the study. To be eligible, patients must have previously received standard systemic therapy, if available, or been unable or unwilling to undergo such treatment. The goal for phase 2 is to enroll up to 120 patients from Asia, Australia, and the United States. For these disease-specific cohorts, patients must have advanced or metastatic disease with 1 or more measurable lesions that has progressed after the most recent treatment.

Although BGB-A425 is a novel agent, tislelizumab is becoming an established part of anticancer therapy. Tislelizumab is approved in China for 5 indications including several first-line NSCLC settings, according to BeiGene Ltd, a pharmaceutical company based in Beijing, China, that is developing both drugs in the regimen.¹⁵ The company is collaborating with Novartis to develop tislelizumab in North America, Europe, and Japan.^15,16 In the United States, the FDA is reviewing a biologics license application for tislelizumab for treating patients with unresectable recurrent locally advanced or metastatic esophageal squamous cell carcinoma after prior systemic therapy. The agency is scheduled to decide on the application by July 12, 2022.¹⁶

Other Partners

In hematologic malignancies, investigators are studying whether there is a role for combining TIM-3 inhibitors with other agents besides ICIs. In May 2021, the FDA granted a fast-track designation for sabatolimab in combination with hypomethylating agents for the treatment of adult patients with myelodysplastic syndromes (MDS) defined as high or very high risk on the Revised International Prognostic Scoring System.¹⁷

Novartis, the company developing the drug, is exploring the efficacy of sabatolimab as part of different combination therapies in patients with MDS and acute myeloid leukemia (AML). The development program includes the phase 2 STIMULUSMDS1 (NCT03946670) and STIMULUS-MDS3 (NCT04812548) studies and the phase 3 STIMULUS-MDS2 (NCT04266301) study in MDS, as well as the phase 2 STIMULUSAML1 study (NCT04150029) in AML.

Line of Therapy in NSCLC

The studies of combination TIM-3 and PD-1/PD-L1 inhibitors underway in NSCLC are recruiting patients who already have received at least 2 lines of therapy. Paul A. Bunn Jr, MD, who served as moderator for the OncLive^® program, wondered about the rationale for not testing the combination in upfront settings, where the regimen might be more effective. He also questioned whether a patient who progressed on ICI therapy would respond to repeat administration of an ICI with an added therapy.

Bunn, a 2014 Giants of Cancer Care^® award winner in the lung cancer category, is the James Dudley Chair in Cancer Research and a distinguished professor of medicine-medical oncology at the University of Colorado School of Medicine in Aurora.

Hirsch agreed that the combination therapy is a candidate for first-line settings but that investigators are still seeking to establish “acceptable safety data” with early-phase studies. “The primary goal so far in this drug development has been to overcome I/O resistance,” he said. “…First-line studies are traditionally in later lines. We might see it in the future when we have a clear picture of the safety and the doses.”

With regard to biomarkers, Hirsch said IHC scoring approaches are “still on a very premature level of development” compared with other immunotherapies and that much more work is needed.

References

1. Acharya N, Sabatos-Peyton C, Anderson AC. Tim-3 finds its place in the cancer immunotherapy landscape. J Immunother Cancer. 2020;8(1):e000911. doi:10.1136/jitc-2020-000911
2. Friedlander A, Addeo A, Banna G. New emerging targets in cancer immunotherapy: the role of TIM3. ESMO Open. 2019;4(suppl 3):e000497. doi:10.1136/esmoopen-2019-000497
3. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168(4):707-723. doi:10.1016/j.cell.2017.01.017
4. Velcheti V, Schalper K. Basic overview of current immunotherapy approaches in cancer. Am Soc Clin Oncol Educ Book. 2016;35:298-308. doi:10.1200/EDBK_156572
5. Wolf Y, Anderson AC, Kuchroo VK. TIM3 comes of age as an inhibitory receptor. Nat Rev Immunol. 2020;20(3):173-185. doi:10.1038/s41577-019-0224-6
6. Solinas C, De Silva P, Bron D, Willard-Gallo K, Sangiolo D. Significance of TIM3 expression in cancer: from biology to the clinic. Semin Oncol. 2019;46(4-5):372-379. doi:10.1053/j.seminoncol.2019.08.005
7. Qin S, Dong B, Yi M, Chu Q, Wu K. Prognostic values of TIM-3 expression in patients with solid tumors: a meta-analysis and database evaluation. Front Oncol. 2020;10:1288. doi:10.3389/fonc.2020.01288
8. Fourcade J, Sun Z, Benallaoua M, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen–specific CD8+ T cell dysfunction in melanoma patients. J Exp Med. 2010;207(10):2175-2186. doi:10.1084/jem.20100637
9. Desai J, Meniawy T, BeagleB , et al. Bgb-A425, an investigational anti-TIM-3 monoclonal antibody, in combination with tislelizumab, an anti-PD-1 monoclonal antibody, in patients with advanced solid tumors: a phase I/II trial in progress. J Clin Oncol. 2020;38:(suppl 15):TPS3146. doi:10.1200/JCO.2020.38.15_suppl.TPS3146
10. TESARO announces immuno-oncology data presentations at SITC 2018 Annual Meeting. News release. TESARO, Inc. November 9, 2018. Accessed November 22, 2021. https://bit.ly/3CJWvUO
11. Davar D, Boasberg P, Eroglu Z, et al. A phase 1 study of TSR-022, an anti-TIM-3 monoclonal antibody, in combination with TSR-042 (anti-PD-1) in patients with colorectal cancer and post-PD-1 NSCLC and melanoma. J Immunother Cancer. 2018;6(suppl 1):O21. doi:10.1186/s40425-018-0423-x
12. Jemperli. Prescribing information. GlaxoSmithKline; 2021. Accessed November 22, 2021. https://bit.ly/30V4kdh
13. Curigliano G, Gelderblom H, Mach N, et al. Phase I/Ib clinical trial of sabatolimab, an anti–TIM-3 antibody, alone and in combination with spartalizumab, an anti–PD-1 antibody, in advanced solid tumors. Clin Cancer Res. 2021;27(13): 3620-3629. doi:10.1158/1078-0432.CCR-20-4746
14. Harding JJ, Moreno V, Bang YJ, et al. Blocking TIM-3 in treatment-refractory advanced solid tumors: a phase Ia/b study of LY3321367 with or without an anti-PD-L1 antibody. Clin Cancer Res. 2021;27(8):2168-2178. doi:10.1158/1078-0432.CCR-20-4405
15. BeiGene pipeline. BeiGene, Ltd. Updated July 13, 2021. Accessed November 22, 2021. https://bit.ly/3qZsM8d
16. BeiGene announces US FDA acceptance of biologics license application for tislelizumab in esophageal squamous cell carcinoma. News release. BeiGene, Ltd. September 13, 2021. Accessed November 22, 2021. https://bit.ly/30MKy3T
17. Novartis receives FDA fast track designation for sabatolimab (MBG453) in myelodysplastic syndromes. Novartis. May 25, 2021. Accessed November 22, 2021. https://bit.ly/3DMfcZm