Targeting TIGIT in lung cancer: will it stick to the wall?

In the past decade immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by blocking the proteins to prevent cancer cells from evading immune response and offering sustained responses and long-term survival benefits across tumor types since the first approval of ipilimumab for melanoma (1). To date, programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitors are indicated in a wide range of different cancers. However, most patients receiving these therapies either alone or in combination do not respond at all (primary resistance) or develop progression of disease over time (secondary resistance), consequently, these patients do not benefit from PD-1/PD-L1 blockade (2). Therefore, how to overcome immune resistance to PD-1/PD-L1 inhibitors has become a great unmet oncologic need. Given the complexity of immune response, it is intuitive to combine immunotherapies to target multiple pathways to achieve a deeper and more durable antitumor immune response as well as to benefit a broader patient population from immunotherapy. This strategy is supported by preclinical studies and has been used successfully in melanoma targeting both PD-1 and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) or lymphocyte-activation gene 3 (LAG-3) (3,4). However, the same combination has not panned out in other tumor types thus far.

T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) belongs to the immunoglobulin superfamily, is an emerging inhibitory receptor expressed mainly on activated CD4⁺ and CD8⁺ T-cells, natural killer (NK) cells as well as regulatory T-cells (Tregs), plays a vital role in regulating adaptive and innate immunity (5-7). TIGIT suppresses T-cell through a variety of inhibitory mechanisms. First, binding of CD155 (PVR)/TIGIT leads to reduction of T-cell receptor expression, causing decreased NK cell and CD8 T-cell effector functions. Second, TIGIT can effectively suppress CD115/CD226-mediated T-cell activation by disrupting dimerization of CD226 and competing against CD115/CD226 binding due to its much higher affinity to CD115 than CD226 (8,9). Third, TIGIT binds to CD115 on antigen presenting cells (APCs) to enhance IL-10 production and diminish IL-12 production, and thus it indirectly impedes T-cell function (7). Last, TIGIT upregulation in Tregs augments their immunosuppressive function and stability (7). TIGIT upregulation in T-cells indicates a poor prognosis in many solid tumors such as lung cancer or melanoma (10,11). In preclinical studies, dual PD-1 and TIGIT blockade has been demonstrated to be a promising combinatorial immunotherapy (10,11).

Kim et al. reported the results of anti-TIGIT antibody tiragolumab as monotherapy or in combination with atezolizumab in patients with advanced solid tumors in JAMA Oncology Nov. 2023 (12). This is an open-label, first-in-human, 1a/1b dose-escalation and dose-expansion, multi-center trial. Patients received fixed-dose intravenous tiragolumab every 3 weeks escalating from 2 to 1,200 mg in phase 1a, or combined with fixed-dose intravenous atezolizumab 1,200 mg every 3 weeks in phase 1b. The primary end points were safety, tolerability, and recommended phase 2 dose (RP2D) for tiragolumab alone or in combination with atezolizumab. 24 patients, 49 patients were enrolled in phase 1a and 1b, respectively. Both tiragolumab alone and combination with atezolizumab were well tolerated, no dose-limiting toxicities (DLTs) occurred. The most common treatment-related adverse events (TRAEs) were fatigue (21% in phase 1a) and pruritus (10% in phase 1b). The RP2D for tiragolumab was 600 mg intravenously every 3 weeks, this dose was further tested in phase 1b dose expansion in combination with atezolizumab. The confirmed overall response rate (ORR) was 0% in phase 1a, with modest antitumor effect in 6% of patients (n=3) in phase 1b. The confirmed ORR in the dose-expansion cohort was 46% (6 of 13) in the non-small cell lung cancer (NSCLC) and 28% (5 of 18) in the esophageal cancer (EC) cohorts without exposure to any prior immunotherapy (12).

These results are in line with two recently reported phase 1 trials using different anti-TIGIT antibodies (13,14). Collectively, the anti-TIGIT therapy is well tolerated either alone or in combination. Immune-mediated adverse events (AEs) such as pruritus and fatigue are more common with combination therapy, but mostly low grade and easy to manage. Anti-TIGIT antibody monotherapy has modest anti-tumor activity, whereas combination with PD-1/PD-L1 blockade are more active particularly in PD-L1 positive NSCLC population (13,14). The hypothesis was further investigated in at least two phase 2 studies (15,16). CITYSCAPE is a phase 2, randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of tiragolumab combined with atezolizumab as first-line therapy in patients with PD-L1 positive advanced NSCLC. A total of 135 patients were enrolled, the benefit with tiragolumab/atezolizumab was more pronounced in the high PD-L1 [Tumor Proportion Score (TPS) ≥50%] population (n=58). The ORR, progression free survival (PFS) was 69% (20/29 patients), 16.6 months for the combo group and 24% (7/29 patients), 4.1 months for the atezolizumab group, respectively. However, similar ORR (16% vs. 18%), PFS (4.0 vs. 3.8 months) in patients with PD-L1 TPS 1–49% (n=77) (15). ARC-7 is another phase 2 trial with a very similar design in untreated advanced NSCLC patients with PD-L1 TPS 1–49%. Combination of domvanalimab, a TIGIT inhibitor, with zimberelimab, a PD-1 inhibitor, improved ORR (26% vs. 15%) and 6-month disease-free survival (DFS, 65% vs. 43%) as compared to zimberelimab alone (16). In both phase 2 studies, high PD-L1 (TPS ≥50%) seems to be a promising surrogate biomarker for TIGIT targeting.

SKYSCRAPER-01 is a global, phase 3, randomized, double-blinded study investigating tiragolumab plus atezolizumab versus atezolizumab alone in 534 patients with treatment-naïve PD-L1-high advanced NSCLC. In view of the robust phase 2 data mentioned above, it was rather surprising to learn that the study missed the co-primary endpoint of PFS and merely showed some numerical improvement in the primary endpoint of overall survival (OS), albeit the data were not mature yet at the time of the second interim analysis (unpublished, press release from the sponsor). The final OS data are eagerly awaited to fully assess the magnitude of benefit from this combination. It is hard to explain the discrepancy in TIGIT performance between these two well-designed studies, CITYSCAPE vs. SKYSCRAPER-01. In CITYSCAPE, although the study is randomized, only 58 patients were included in the subset (TPS ≥50%) analysis. PD-L1 is not a perfect biomarker and TPS ≥50% is an arbitrary cutoff, unsurprisingly, the ORR varies significantly among studies using atezolizumab treating NSCLC patients with the same PD-L1 cutoff (15). It is also conceivable that factors such as mutation status (KEAP1, STK11) or tumor microenvironment other than TIGIT inhibition might have contributed to the biased results of the small subset analysis in CITYSCAPE. Consequently, SKYSCRAPER-01 could not replicate the CITYSCAPE results.

The phase 3 SKYSCRAPER-02 trial is a global, double-blind trial, a total of 490 patients with newly diagnosed extensive-stage small cell lung cancer (ES-SCLC) were randomly assigned to receive either chemotherapy with atezolizumab with placebo or tiragolumab. This is the first published phase 3 study evaluating the role of targeting TIGIT in immuno-oncology. The results were reported in the Journal of Clinical Oncology, which demonstrated absolutely no difference in PFS or OS. Median OS was the same, 13.1 months in both groups (17). Compared with NSCLC, SCLC has relatively lower PD-L1 expression and the response to PD-1/PD-L1 blockade does not correlate with PD-L1 expression. Nonetheless this study casts some shadow in the efficacy of dual blockade of PD-1/PD-L1 and TIGIT simultaneously.

As one of many immune checkpoints, TIGIT has undoubtedly drawn an enormous interest in post-PD-1/PD-L1 era. Up to date, there are over 30 anti-TIGIT antibodies in development and more than 120 clinical trials on going (1). The enthusiasm and effort are commendable, yet the all-comer approach is becoming increasing questionable. The most important lesson we have learned from the success of precision oncology lies in our great understanding of targetable mutations. An ongoing “Throw spaghetti at the wall and see what sticks” approach will be proven futile when it comes to most of the next-generation ICIs including TIGIT inhibitors in lung cancer clinical trials. The field urgently calls for a fundamental understanding of the role of next-generation ICIs in the context of resistance to PD-1/PD-L1 blockade and better predictive biomarkers for successful trial design.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-24/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-24/coif). J.N. served as an advisory board of AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Johnson & Johnson, Merck, Pfizer, Sanofi, Takeda. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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