Immunotherapy treatments have generated excitement by eliciting durable responses in various tumor types, making a significant contribution to the progress of oncology.1,2 However, monotherapy with anti–PD-1/PD-L1 and anti–CTLA-4 monoclonal antibodies has yielded low response rates, mainly due to insufficient immune activation.1,3 There is hope that these poor monotherapy response rates will significantly improve when these agents are combined with T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) inhibitors, which are next-generation immune checkpoint antibodies (FIGURE 14).
“I do believe that PD-1 and PD-L1 inhibitors are really the first step in understanding how a cancer interacts with a patient’s immune system,” said Melissa Johnson, MD, program director of lung cancer research and of the Solid Tumor Immune Effector Cellular Therapy Program at Sarah Cannon Research Institute in Nashville, Tennessee, in an interview with Targeted Therapies in Oncology (TTO). “There’s so much more to learn, and there are many patients who aren’t benefiting from PD-1/ PD-L1 inhibitors. We owe it to them especially to keep looking and to keep evaluating strategies that would also stimulate their immune system in the same way.”
To increase response rates, immune checkpoint inhibitors have been used in combination with chemotherapy or other immune checkpoint inhibitors, although this strategy has led to more adverse events (AEs).1 Additionally, although some patients with metastatic melanoma have seen increased response rates with the combination of ipilimumab (Yervoy) and nivolumab (Opdivo) compared with either monotherapy, a substantial number of patients remained unresponsive. In an area of ongoing research, combinations of immune checkpoint inhibitors are being evaluated for their ability to further stimulate the immune system.
“It is clear that only a small subset of patients respond to PD-1 [inhibitors] alone. Understanding how to use the other immune cells, particularly the Tregs, which regulate other cells in the immune system, to jump-start immunotherapy makes good sense and is an avenue we are excited about,” Jyoti Patel, MD, said in an interview with TTO. Patel is a professor of medicine and the associate vice chair for clinical research in the Department of Medicine at Northwestern University Feinberg School of Medicine and the medical director of thoracic oncology and assistant director for clinical research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, Illinois.
Recent research has identified TIGIT as a promising emerging immune checkpoint target. TIGIT indirectly suppresses T-cell activation and is expressed on multiple types of immune cells, including regulatory T (Treg) cells, activated T cells, and natural killer (NK) cells.1,5 TIGIT is upregulated in T cells and NK cells after ligand binding, inhibiting these cells’ ability to kill tumor cells.2 Increased TIGIT expression is also associated with advanced disease and poor survival outcomes. Additionally, increased TIGIT expression after treatment is associated with disease recurrence. TIGIT and its coreceptors, including CD226 and CD96, interact with a group of ligands expressed on tumor cells: nectins and nectin-like molecules, including poliovirus receptor (PVR), the main TIGIT ligand. PVR ligands binding to TIGIT suppresses the antitumor immune response of the TIGIT-expressing cell; in contrast, ligand binding to CD226 triggers immune cell activation. Thus, TIGIT and CD226 oppose each other to regulate tumor immunity.1,2 Anti-TIGIT therapy is presumed to invigorate immune function and enhance the activity of T cells and NK cells.2
The most promising data have come from tiragolumab, an anti-TIGIT antibody, in combination with atezolizumab (Tecentriq), an anti–PD-L1 antibody. Immunotherapy combinations featuring dual blockade of TIGIT and PD-1/PD-L1 are promising due to their synergistic enhancement of antitumor responses.1,6
“We have great comfort and a lot of options with checkpoint inhibitors targeting PD-1 and PD-L1, but it seems that [targeting the TIGIT] pathway in this combinatorial approach will be well tolerated, unlike using CTLA-4 with PD-L1,” Patel said. “Anti-TIGIT therapy is exciting because we see it as a complement with PD-1 blockade in the wide variety of tumors in which we’ve seen efficacy. It seems that by inhibiting TIGIT, we may again improve PD-1 efficacy.”
Tiragolumab was the first anti-TIGIT antibody to receive the FDA’s breakthrough therapy designation, based on findings from the CITYSCAPE trial (NCT03563716).7 CITYSCAPE (n = 135) was a prospective, randomized, double-blind, placebo-controlled, phase 2 trial in patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) who were chemotherapy naive with PD-L1positive status (percentage of tumor cells expressing PD-L1 or tumor proportion score [TPS], ≥ 1%) and wild-type EGFR and ALK.8 Results demonstrated that the objective response rate (ORR) was improved in patients randomized to the tiragolumab and atezolizumab (TA) group (n = 67) compared with the placebo and atezolizumab (PA) group (n = 68), at 37.3% versus 20.6%, respectively (odds ratio, 2.57; 95% CI, 1.07-6.14). Patients in the TA group also had improved median progression-free survival (mPFS) compared with PA (5.6 months vs 3.9 months; HR, 0.57; 95% CI, 0.37-0.90).
“Although there have been other checkpoint inhibitors that have been developed to try to amplify the antitumor immune response achieved by PD-1 and PD-L1 inhibitors, there are very few that actually work,” Johnson said. “The CITYSCAPE data presented at ASCO [American Society of Clinical Oncology meeting] in 2020 showed that the addition of the anti-TIGIT tiragolumab to atezolizumab improved responses and progression-free survival in patients who had PD-L1–expressing tumors. [The results of CITYSCAPE] suggest there is, in fact, a way to push those tumors that are immune sensitive a little bit further.
“Perhaps the most impressive thing about the CITYSCAPE data was the exploratory analysis in the [patients with] PD-L1–high [tumors, which] express PD-L1 at greater than 50%. The response rates were 66% in the combination group and 24% in atezolizumab alone. The [median] PFS was not reached when patients were treated with the combination, and it was 4 months for patients treated in the atezolizumab arm, suggesting that the [patients with] PD-L1–high [tumors] are the ones [who] benefit the most from [a TIGIT and PD-L1 blockade] strategy,” Johnson continued.
The safety profiles of the 2 groups in CITY-SCAPE were comparable.8 Most patients in both groups experienced treatment-related AEs (TRAEs), 80.6% in the TA group and 72% in the PA group.
“The most common [adverse] effects were what you would expect from immune-mediated therapy, like rash and thyroid issues,” Johnson said. “Most commonly, infusion reactions were seen, and that typically was with the first dose only and not with subsequent infusions. Some soft stool and diarrhea [were reported as well]. There were very few cases of more severe immune- related toxicities, like hepatitis.”
“The toxicity seems quite manageable, and we’re seeing improvements in both progression-free survival and response,” Patel added.
“My sense is that we can expect the [combination of tiragolumab and atezolizumab to be used in future practice] without toxicity rates of 30% like we’ve seen for ipilimumab and nivolumab. I think that’s certainly led to enthusiasm in larger phase 3 studies,” she said.
Several trials are currently evaluating the use of tiragolumab in different combinations in the frontline setting to determine the efficacy of TIGIT and PD-1/PD-L1 combination therapy.
“I could envision that [tiragolumab] could be added to the armamentarium in a lot of ways,” Johnson said. “It just depends on what some of these trials show us about where the benefit is the greatest.…There are lots of things that one can do with a checkpoint inhibitor once you figure out where it’s the most useful. It’s an exciting discovery.”
One notable tiragolumab trial, SKY-SCRAPER-01 (NCT04294810), is a double-blind, randomized, placebo-controlled, phase 3 trial evaluating the frontline use of tiragolumab and atezolizumab compared with placebo and atezolizumab in advanced, PD-L1–high NSCLC. The trial is expected to enroll 560 patients, with primary outcomes of PFS and overall survival (OS).
“The SKYSCRAPER-01 trial that’s enrolling right now in frontline lung cancer is a really important trial. [The trial investigators hope] to see a significant difference between atezolizumab and tiragolumab compared with atezolizumab alone,” Johnson said.
Another anti-TIGIT antibody with encouraging results in NSCLC is vibostolimab. The ongoing, multicohort, phase 1 MK-7684-001 trial (NCT02964013) is evaluating vibostolimab in patients with advanced solid tumors, and results from the dose-confirmation/expansion phase in patients with NSCLC were recently published. One report described evaluation of vibostolimab as either monotherapy or in combination with pembrolizumab (Keytruda) in 79 heavily pretreated patients with anti–PD-1/PD-L1–refractory disease.9 The majority of patients (78%) had received at least 2 prior lines of therapy. The ORR was 7% (95% CI, 2%-20%) for vibostolimab monotherapy (n = 41) and 5% (95% CI, <1%-18%) for combination therapy (n = 38). AEs occurred in at least 97% of patients, and at least 65% experienced TRAEs. Common TRAEs included pruritus, fatigue, rash, arthralgia, and decreased appetite. Grade 3 to 4 TRAEs occurred in 10 patients, with lipase increase and hyper-tension being the most common.
Discussing the optimal sequencing of checkpoint inhibitors in therapy, Johnson said, “what we’re finding with lots of check-point inhibitors is that it’s not enough to restore an immune response to a cancer that has developed resistance to a PD-1 inhibitor alone.…We’ll have to find other therapies for patients with acquired resistance to PD-1 inhibitors, rather than trying to continue them and add other checkpoint inhibitors to them. I don’t think there’s been much success with many checkpoint inhibitors [used as therapy for PD-1– or PD-L1–refractory disease].”
In another report of results from the MK-7684-001 study, 41 anti–PD-1/PD-L1–naive patients with advanced NSCLC all received the vibostolimab-pembrolizumab combination.10 The majority of patients (73%) had received at least 1 prior treatment regimen. Results demonstrated an ORR of 29% (95% CI, 16%-46%). Patients with PD-L1–positive tumors (TPS ≥ 1%) had an ORR of 46% (95% CI, 19%-75%), whereas their PD-L1–negative counterparts (TPS < 1%) had an ORR of 25% (95% CI, 5%-57%).
The mPFS for the entire cohort was 5.4 months (95% CI, 2.1-8.2). PD-L1–positive patients had an mPFS of 8.4 months (95% CI, 3.9-10.2), double the PD-L1–negative mPFS of 4.1 months (95% CI, 1.9-not reached). TRAEs occurred in 83% of patients, with the most common being pruritus, hypoalbuminemia, and pyrexia. Serious grade 3 to 4 TRAEs occurred in 15% of patients. Investigators concluded that the combination therapy was well tolerated and had promising antitumor activity.
“Vibostolimab has certainly caught our attention…seeing [that] the drug was well tolerated and improved response rates,” Patel said.
Another noteworthy anti-TIGIT antibody is domvanalimab. This agent is currently being evaluated in patients with PD-L1–positive, locally advanced or metastatic, treatment-naive NSCLC in the ARC-7 trial (NCT04262856).
This open-label, randomized phase 2 trial includes 3 study arms: zimberelimab (anti–PD-1) monotherapy, domvanalimab with zimberelimab, and domvanalimab with zimberelimab and etrumadenant (a dual–adenosine receptor antagonist). The study is expected to enroll approximately 150 patients (FIGURE 2).
Multiple new anti-TIGIT antibodies are in the pipeline. Data presented at the American Association for Cancer Research Annual Meeting 2021 highlighted early-phase clinical and preclinical trials evaluating TIGIT- targeting antibodies.
“There are other TIGIT antibodies…and whether they work the same or not, we’re still learning,” Johnson said.
EOS884448 (EOS-448) is a potent anti-TIGIT antibody that was evaluated as monotherapy in a multicenter, open-label, phase 1/2 study in patients with previously treated advanced solid malignancies (NCT04335253). Preliminary dose-escalation results (n = 22) demonstrated no dose-limiting toxicity at any of the 5 dose levels tested and pharmacokinetic analyses indicated dose-proportional increases in plasma EOS-448.11 The patients received EOS-448 intravenously once every 2 weeks or once every 4 weeks according to their dose and schedule allocation. Doses of 20, 70, 200, 700 mg once every 2 weeks and 1400 mg every 4 weeks were evaluated. Depletion of suppressive Treg cells was observed at all dose levels. Additionally, the optimal dosing interval was found to be every 3 or 4 weeks. Patients had received a median of 3 lines of therapy prior to treatment with EOS-448.
Investigator assessment of 20 response-evaluable patients demonstrated stable disease in 9 patients and a partial response in 1 patient with melanoma previously treated with pembrolizumab. No immunogenicity was observed in any patients. Treatment-related AEs (TEAEs) occurred in 82% of patients, with pruritus, infusion- related reaction, fatigue, and pyrexia being the most common. The majority (52%) of patients with TEAEs had grade 3 or higher, with serious TEAEs occurring in 36%. Investigators concluded that these preliminary data support further exploration of EOS-448 in clinical trials.
One tumor type of interest in TIGIT research is breast cancer. Triple-negative breast cancer (TNBC) is a particular focus because immunotherapy has proven highly beneficial in that patient population. Additionally, there is increased expression of TIGIT in malignant breast tissue compared with normal tissue, further highlighting the potential for use of TIGIT-targeting therapeutics in this patient population.
Another study evaluated mRNA expression of members of the TIGIT/PVR/NECTIN family in breast tumors from 1904 patients using a publicly available data set.12
Comparison of results in different breast cancer subtypes demonstrated that most TIGIT/PVR/NECTIN genes had the highest expression levels in TNBC, followed closely by HER2-positive breast cancer. Hormone receptor–positive breast cancer had the lowest expression. No association was found between expression of most TIGIT/PVR/ NECTIN genes and OS across breast cancer subtypes. However, expression of the costimulatory receptor CD226 was associated with significantly improved OS in early TNBC (HR, 0.69; 95% CI, 0.48-0.99).
The investigators concluded that combination therapy targeting TIGIT and PD-1/ PD-L1 may provide improved efficacy in patients with TNBC.
“In triple-negative breast cancer, there’s been some question about the efficacy of immunotherapies,” Patel said. “Many of these tumors may look cold, and inhibition of TIGIT, which is suppressing the immune reaction, might make sense to make [the tumor microenvironment] more immune favorable.”
HLX53 is a novel single-domain antibody that binds TIGIT strongly, blocking binding of its ligands CD155 (NECTIN5) and CD112 (NECTIN2), thus preventing TIGIT from inhibiting the antitumor immune response. Combining HLX53 with an anti–PD-L1 antibody showed a synergistic effect on tumor inhibition.13
Another anti-TIGIT antibody with promising preclinical data is SEA-TGT.14 Its distinct, nonfucosylated antibody backbone was shown to confer enhanced antitumor activity, including Treg depletion, compared with standard-format anti-TIGIT antibodies.
A phase 1 trial (NCT04254107) has been initiated to investigate SEA-TGT alone and in combination with pembrolizumab. The study protocol was presented at the 2021 ASCO Annual Meeting.
Other anti-TIGIT therapies include etigilimab and BMS-986207. Etigilimab is currently undergoing evaluation with nivolumab in an open-label, multicenter, phase 1/2 basket study (NCT04761198) in patients with advanced solid tumors. This trial has an estimated enrollment of 125 patients.
In another phase 1/2 open-label trial (NCT04570839), BMS-986207 is being evaluated in combination with nivolumab and COM701, an inhibitor of PVRIG (a TIGIT coreceptor that binds NECTIN2). To be eligible for study, patients must have high tumor expression of NECTIN2. The investigators plan to accrue 100 patients with advanced solid tumors for the trial.
“There are a number of exciting compounds. Right now they seem to be improving response rates compared with PD-L1 inhibitors or PD-1 inhibitors alone,” Patel said.
“I think…we need to see more mature data in a larger group of patients and actually have [an] eye toward the patient selection for these compounds because [they are] clearly efficacious. We just have to understand in whom monotherapy would be more effective [compared with combination therapy].”
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