Thao K . Huynh, PharmD , BCOP

Immunotherapy treatments have generated excitement by eliciting durable responses in various tumor types, making a significant contribution to the progress of oncology.

 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.

 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 (

“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 

. “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).

 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 

. 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.

 TIGIT is upregulated in T cells and NK cells after ligand binding, inhibiting these cells’ ability to kill tumor cells.

 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.

 Anti-TIGIT therapy is presumed to invigorate immune function and enhance the activity of T cells and NK cells.

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.

“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).

 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 

 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.

 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.

 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 (

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.

 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.

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.

Another anti-TIGIT antibody with promising preclinical data is SEA-TGT.

 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].”

1. Rotte A, Jin JY, Lemaire V. Mechanistic overview of immune checkpoints to support the rational design of their combinations in cancer immunotherapy. 

2018;29(1):71-83. doi:10.1093/ annonc/mdx686 

2. Yeo J, Ko M, Lee DH, Park Y, Jin HS. TIGIT/CD226 axis regulates anti-tumor immunity. 

3. Ventola CL. Cancer immunotherapy, part 3: challenges and future trends. 

4. Gorvel L, Olive D. Targeting the “PVR-TIGIT axis” with immune checkpoint therapies. 

2020;9:F1000 Faculty Rev-354. doi:10.12688/f1000research.22877.1 

5. Qin S, Xu L, Yi M, Yu S, Wu K, Luo S. Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4. 

 2019;18(1):155. doi:10.1186/s12943-019-1091-2 

6. Chauvin JM, Zarour HM. TIGIT in cancer immunotherapy. 

2020;8(2):e000957. doi:10.1136/jitc-2020-000957 

7. Roche’s novel anti-TIGIT tiragolumab granted FDA breakthrough therapy designation in combination with Tecentriq for PD-L1-high non-small cell lung cancer. News release. Roche. January 5, 2021. Accessed April 26, 2021. https://bit.ly/3hmWDm3 

8. Rodriguez-Abreu D, Johnson ML, Hussein MA, et al. Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). 

 2020;38(suppl 15):9503. doi:10.1200/JCO.2020.38.15_suppl.9503 

9. Ahn M, Niu J, Kim D, et al. Vibostolimab, an anti-TIGIT antibody, as monotherapy and in combination with pembrolizumab in anti-PD-1/PD-L1-refractory NSCLC. 

 2020;31(suppl 4):S887. doi:10.1016/j.annonc.2020.08.1714 

10. Niu J, Nagrial A, Voskoboynik M, et al. Safety and efficacy of vibostolimab, an anti-TIGIT antibody, plus pembrolizumab in patients with anti-PD-1/PD-L1-naive NSCLC. 

2020;31(suppl 4):S891-S892. doi:10.1016/j.annonc.2020.08.1724 

11. Van den Mooter TFA, Migeotte A, Jungles C, et al. Preliminary data from phase I first-in-human study of EOS884448, a novel potent anti-TIGIT antibody, monotherapy shows favorable tolerability profile and early signs of clinical activity in immune-resistant advanced cancers. Poster presented at: American Association for Cancer Research (AACR) Annual Meeting 2021; April 10-15, 2021; virtual. 

12. DuPree K, Molinero L. TIGIT/PVR/NECTIN immune checkpoint axis expression across breast cancer subtypes. Poster presented at: AACR Annual Meeting 2021; April 10-15, 2021; virtual. 

13. Hua B, Yang M, Xue J, et al. A novel single-domain antibody targeting TIGIT for cancer use in combination therapies. Poster presented at: AACR Annual Meeting 2021; April 10-15, 2021; virtual. 

14. Smith A, Zeng W, Lucas S, et al. SEA-TGT is an empowered anti-TIGIT antibody that displays superior combinatorial activity with several therapeutic agents. Poster presented at: AACR Annual Meeting 2021; April 10-15, 2021; virtual.

Articles

Approaches that pair anti-TIGIT antibodies with other immune checkpoint inhibitors  have sparked interest among investigators. Results of early-stage studies evaluating these unique combinations were recently presented at the American Association for Cancer Research Annual Meeting 2021. Later-stage studies are ongoing.

Anti-TIGIT and ICI Combinations Supported by Early-Phase Research

Addressing tumor molecular heterogeneity is a challenge, especially when designing effective biomarker-driven treatment strategies. Research characterizing the relationship between this heterogeneity and response to targeted therapies can lead to improved selection of patients who will benefit from specific therapies. This, in turn, may improve response rates to targeted therapies, some of which have been disappointingly low in unselected patient populations.

“We recognize that many differences exist [in genomic alterations between different patients with gastroesophageal adenocarcinoma], something we call interpatient molecular heterogeneity, and that has led to some hurdles in trying to study given genetic events and matched targeted therapy, especially when it involves a smaller subset of the whole … and [it] has been prohibitive and difficult to accomplish in many situations or scenarios,” said Daniel Catenacci, MD, during an interview with 

. He is associate professor of medicine and director of the GI oncology program at the University of Chicago in Illinois.

Basing therapy selection in metastatic gastroesophageal adenocarcinoma (GEA) on analysis of the primary tumor alone may be suboptimal because of intrapatient heterogeneity of key clinical biomarkers; according to published reports, genomic profiling discrepancies between the primary tumor and lymph node metastases are observed in approximately 30% to 50% of cases.1,2 The extent of genomic variability in patients with newly diagnosed metastatic GEA was evaluated in a study using sequencing to compare genomic alterations between the primary tumor and paired metastatic lesions.

 In cohort 1 (n=11 patients), a comparison between primary tumors and metastases at baseline revealed discrepant pathogenic alterations between the 2 sites in 45% of patients. Evaluation of samples from multiple regions of the primary tumor and metastatic sites in cohort 2 (n=26 patients) demonstrated striking heterogeneity both within the primary tumor and between primary and metastatic sites. In cohort 3 (n=11 patients), circulating tumor DNA (ctDNA) from blood plasma was compared with standard primary tumor samples. The results revealed genomic alterations present in the primary tumor but not in the ctDNA, and vice versa. Overall, given the wide extent of tumor heterogeneity, this study’s findings highlighted the importance of performing biomarker profiling on samples from several regions of multiple tumor sites to optimize targeted therapy selection in trials for metastatic GEA.

“One strategy to address [the limitation of infrequent driver alterations] has been to use basket studies or a tissue-agnostic approach that pooled [results] across different tumor types. As long as tumors had a given genetic mutation, you would be able to enroll patients to that cohort,” said Catenacci.

Expansion platform designs have been evaluated for clinical trials of targeted therapies in oncology, with the majority employing type I expansion platform designs. These “umbrella trials” assign patients to cohorts that pair a specific tumor molecular profile with a matched targeted treatment. Because each cohort has an individual end point, a large sample is typically required for sufficient statistical power.1 “The limitations of type I expansion platform designs [include] that generally, they have been testing 1 drug, a monotherapy. It has been hard to combine therapies, especially standard therapy or chemotherapy, which differs across tumor types. It is hard to design such studies, so by default [the patient population in the study is heavily pretreated and receiving monotherapy, which is suboptimal]. In addition to that, there are still usually small cohorts and nonrandomized trials,” Catenacci said.

Alternatively, type II expansion platform designs pool multiple biomarker-drug pairings, allowing for smaller sample sizes. Successful type II trial design depends on use of a correct predefined treatment algorithm, appropriate biomarker-drug pairings, and validated companion diagnostics. Type II expansion platform designs can either be histology dependent (type IIA) or histology agnostic (type IIB).

An example of a type IIA expansion platform design is the PANGEA study (NCT02213289).

 This phase 2, open-label, single-arm trial aimed to address molecular heterogeneity at baseline and upon disease progression using a personalized treatment strategy (FIGURE3,4). Patients with newly diagnosed advanced GEA were included in the study, regardless of biomarker status. Biomarker profiling was performed on primary tumor and metastatic biopsies at baseline, upon first disease progression, and upon second disease progression. Testing of ctDNA, a noninvasive means of biomarker analysis, was performed at baseline and at each point in disease progression. Eight treatment groups were paired with 6 therapeutic targeted monoclonal antibodies.

“An important point to note is that in the biomarker groups, there’s overlap in a given patient, so a single patient’s tumor could fall into more than 1 group in our study. We prioritized the biologic groups such that if a patient’s tumor did fall into more than 1 group, then we had already prespecified what would happen in this treatment algorithm, [making] this more reproducible by others,” Catenacci said.

“Our strategy was that all patients screened would [receive a targeted antibody], and it would be prioritized based on their biology and tested prospectively,” Catenacci added.

All patients in the study received chemotherapy in combination with targeted monoclonal antibody therapy based on biomarker analysis. In the event of discordant biomarker profiles between the metastatic site and the primary tumor, the former took precedence in treatment assignment. Reassignment to a new line of sequential therapy based on biomarker analysis could occur at each point in disease progression.

Of 80 enrolled patients, 68 were included in the intention-to-treat (ITT) analysis. The primary efficacy end point was met, with 1-year overall survival (OS) of 69.4% (

 The median OS was 16.4 months (95% CI, 13.8-20.8).

 Median OS for the ITT patients was significantly longer in the higher-priority biological groups (1-4) compared with the lower-priority groups (6-8), at 25.8 months vs 13.9 months, respectively (

 At baseline, spatial heterogeneity was observed in 37% of patients, who had discordant molecular profiles between primary and metastatic tumors.

 Of the 55 patients in the modified ITT group who progressed on first-line therapy, 27 (49%) were assigned to a different biomarker group for second-line therapy due to temporal biomarker evolution. Similarly, 13 of 27 patients (48%) with second-line progression changed group assignment for third-line treatment. This novel treatment strategy, with sequential antibody assignments matched to biomarker profiles, demonstrated improved efficacy outcomes in GEA compared with historical controls.

“A limitation of [type II expansion platform design] is that just because the strategy is considered successful in a positive study doesn’t necessarily mean that each subarm of the study contributed to that outcome… that’s why we looked at the outcome by arm, [which was] prespecified to show that each arm was at least contributing in some way to the outcome,” Catenacci said.

Cathy Eng, MD, professor of medicine (hematology and oncology), codirector of GI oncology, and coleader of the Gastrointestinal Cancer Research Program at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, commented that PANGEA featured “an innovative approach. I think looking at resistance and how to provide sequencing of therapy is the most interesting [concept from the trial] from my perspective as a clinician and clinical researcher.”

An example of a type IIB expansion platform design is SHIVA (NCT01771458), the first study to evaluate off-label use of molecularly targeted agents. This open-label, randomized, multicenter, phase 2 trial included patients with any metastatic solid malignancy refractory to standard-of-care therapy.5 Patients with tumor genetic alterations in hormone receptor, PI3K/AKT/mTOR, or RAF/MEK pathways were randomized to receive either 1 of 11 matched targeted agents (experimental group; n = 99) or physician’s choice of treatment (control group; n = 96). The median progression-free survival (PFS) was 2.3 months in the experimental group and 2.0 months in the control group, (HR, 0.88; 95% CI, 0.65-1.19; 

 = .41). Although the trial did not demonstrate improved PFS with the use of targeted agents outside their approved indications, it was a pivotal step in the exploration of type II expansion platform study design.

“A limitation is that the conclusion [of the SHIVA trial] should not be that subarms are negative,” Catenacci said. “The conclusion should be that the overall approach was negative…There may have been 1 or more subgroups within that SHIVA strategy that are in fact truly better, yet they have to be proven in a different way or [with] a different strategy.”

Despite the acknowledged limitations to the type II expansion platform design, it has several benefits, including the ability to evaluate tumor evolution over time and to incorporate sequential treatment after disease progression.

 Another benefit of the type II expansion platform design is that it allows for a small sample size, which is typically a barrier when studying uncommon molecular alterations. A smaller sample size is allowed because results are pooled within a single trial. Because patients receive maximum exposure to the appropriate agents, a smaller sample size is needed to achieve statistical significance.

Type II expansion platform trials are advantageous for patients because there is a plan from the beginning, Eng said, “so it brings confidence to the patients. Also, the patient is being followed by the same research team, [which I] think is to the patient’s advantage…It’s not like a randomized phase 3 study [in which the patient is] switched from one trial to another trial [after disease progression] and you’re only following the patient for overall survival.”

One example of a trial with a traditional design is RAINFALL (NCT02314117), a randomized, placebo-controlled, double-blind, multicenter, phase 3 trial in patients with metastatic GEA. Patients received fluoropyrimidine and cisplatin plus either ramucirumab (Cyramza; n=326) or placebo (n=319).

 Median PFS was significantly longer in the ramucirumab group (5.7 months) compared with the placebo group (5.4 months; HR, 0.753; 95% CI, 0.607-0.935; 

RAINFALL, Catenacci said, was “what I would call a traditional phase 3 study. It wasn’t selecting patients based on any biology to predict benefit of a given drug and just assessing to see if it was better.”

Various factors are considered when choosing the appropriate design for a clinical trial, Catenacci said. “It’s dependent on disease type, on details of the setting that is being investigated, and on the drugs that are going to be investigated. The hypothesis associated with some drugs may be that they work similarly across all subgroups of a given disease, and in that case, a traditional study would make a lot of sense. On the other hand, if there are drugs that are only hypothesized to work in certain select situations and biological circumstances within a disease, then that’s where an expansion platform design might be more useful.”

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. 2015;9(5):967-996. doi:10.1016/j.molonc.2014.09.011 

2. Pectasides E, Stachler MD, Derks S, et al. Genomic heterogeneity as a barrier to precision medicine in gastroesophageal adenocarcinoma. 

. 2018;8(1):37-48. doi:10.1158/2159-8290.CD-17-0395 

3. Catenacci DVT, Moya S, Lomnicki S, et al. Personalized Antibodies for Gastroesophageal Adenocarcinoma (PANGEA): a phase II study evaluating an individualized treatment strategy for metastatic disease.

. 2021;11(2):308-325. doi:10.1158/2159-8290.CD-20-1408 

4. Catenacci DVT, Lomnicki S, Chase L, et al. Personalized ANtibodies for GastroEsophageal Adenocarcinoma (PANGEA): primary efficacy analysis of the phase II platform trial (NCT02213289). 

. 2020;38(suppl 4):abstr 356. doi:10.1200/JCO.2020.38.4_suppl.356 

5. Le Tourneau C, Delord J-P, Gonçalves A, et al; SHIVA Investigators. Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial. 

. 2015;16(13):1324-1334. doi:10.1016/S1470-2045(15)00188-6 

6. Fuchs CS, Shitara K, Di Bartolomeo M, et al; RAINFALL Study Group. Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial. 

. 2019;20(3):420-435. doi:10.1016/S1470-2045(18)30791-5

Research characterizing the relationship between this heterogeneity and response to targeted therapies can lead to improved selection of patients who will benefit from specific therapies.

GI Study Addresses Tumor Molecular Heterogeneity Using Unique Trial Designs

Although chemotherapy is the mainstay of systemic treatment for advanced cholangiocarcinoma (CCA), there are limited treatment options when the disease progresses. Investigators are evaluating multiple studies that are focused on targeted therapies in this setting, and the results appear positive.

“This is a disease where every single day I feel we’re making meaningful progress, and it’s exciting to be part of this world right now because you can see the forward motion happening,” Rachna Shroff, MD, associate professor in the Department of Medicine, Division of Hematology and Oncology, and chief of gastrointestinal medical oncology at the University of Arizona Cancer Center in Tucson, said in an interview with T

Next-generation sequencing (NGS) has identified multiple targetable oncogenes in CCA. Approximately 45% of patients with intrahepatic cholangiocarcinoma (iCCA) have actionable genetic alterations with fibroblast growth factor receptor 2 (

) fusions or rearrangements occurring exclusively in iCCA.

“Cholangiocarcinoma is a very target-rich disease. From day 1, we need to understand the genetic landscape of this cancer [and patients should have NGS data],” Tanios S. Bekaii-Saab, MD, professor of medicine and consultant, Division of Hematology/ Oncology at Mayo Clinic in Phoenix, Arizona, said in an interview with 

FGF/FGFR is a signaling pathway responsible for regulating cell survival and mediating physiological functions. If the FGF/FGFR pathway is disrupted due to genetic alterations, malignancies may arise, including CCA.1 FGFR2 gene fusions or rearrangements are the most common oncogenic drivers in iCCA, accounting for approximately 13% of mutations.1,3 “Although this is a rare tumor with a rare subset, it [comprises] a meaningful percentage of patients in a disease that otherwise has very limited therapeutic options,” Shroff said.

Recently, the development of FGFR inhibitors has provided a promising class of agents in the treatment of CCA, especially since 

 fusion may not respond better to chemotherapy compared with 

 Results from a retrospective analysis demonstrated that survival outcomes in patients with iCCA harboring 

 fusions (n = 15) have similar median progression-free survival (PFS) compared with 

 wild type (n = 107), 6.2 months (95% CI, 2.0-16.8) versus 7.2 months (95% CI, 5.0-8.3) for firstline standard chemotherapy treatment, respectively.

 fusions and subsequent inhibition with targeted therapy [are] of great interest in cholangiocarcinoma primarily because we have multiple trials as proof of principle that we can effectively target this pathway,” Shroff said.

Three Agents in Development There are currently 3 FGFR inhibitors that treat CCA. Pemigatinib (Pemazyre) is the first FDA-approved agent for CCA based on results from the FIGHT-202 clinical trial (NCT02924376).

 FIGHT-202 is a phase 2, single-arm, multicenter, multicohort trial that evaluated the safety and efficacy of pemigatinib in previously treated, locally advanced, or metastatic CCA.5 In 107 patients evaluated with 

 fusions, the objective response rate (ORR) was 35.5% (95% CI, 26.5%-45.3%). The median duration of response (DOR) was 7.5 months (95% CI, 5.7-14.5) with disease control rate (DCR) of 82.2%. The median PFS was 6.9 months (95% CI, 6.2-9.6), and preliminary median OS was 21.1 months (95% CI, 14.8-not estimable).

Other FGFR inhibitors evaluated after progression on chemotherapy include infigratinib and futibatinib. Infigratinib was evaluated in advanced CCA in a single-arm, phase 2 trial (NCT02150967) in patients harboring 

 fusions presented at the 2021 Gastrointestinal Cancers Symposium. Approximately 160 patients are to be enrolled in 3 cohorts, with results from cohort 1 (n = 108) presented at the conference. ORR was observed in 23.1% (95% CI, 15.6-32.2). The ORR was higher in the second-line setting compared with third or later lines, 34% versus 13.8%, respectively. The median PFS was 7.3 months (95% CI, 5.6-7.6), and DOR was approximately 5 months (range 0.9-19.1).

Commenting on the studies with pemigatinib and infigratinib, Shroff said, “More [patients in] the infigratinib patient population have progressed on multiple lines of chemotherapy [compared with] pemigatinib. [Approximately] 60%…received pemigatinib as second-line therapy, so a little earlier than what we saw in the infigratinib data.”

Shroff added, “Interestingly, it seems the earlier use of FGFR inhibitors, in the second line for instance, produces a slightly higher response rate, suggesting that there’s utility in moving this targeted therapy into the earlier [lines of treatment].”

The third agent of interest is futibatinib, a third-generation, irreversible FGFR inhibitor. In the phase 2 FOENIX-CCA2 trial (NCT02052778), futibatinib was evaluated in 103 previously treated patients harboring 

 fusion. Data were included for 67 patients with an observed ORR of 37.3%, DCR of 82.1%, and median DOR of 8.3 months.

Adverse Effects One of the challenges of FGFR inhibitors is the associated toxicities. Adverse effects of various FGFR inhibitors are very similar due to the class effect of FGFR inhibition.

Bekaii-Saab noted, “The [adverse event] that’s very prominent or common is hyperphosphatemia, which does occur in approximately half of patients, although [there were no severe grade toxicities associated with it]. [Hyperphosphatemia] can be managed with a low phosphate diet. Occasionally we use phosphate binders and rarely we require dose reductions or interruptions.”

Shroff noted, “I think what we’ve learned is that [although] we were aggressive in managing [hyperphosphatemia], clinically it did not produce a lot of major issues.”

Other common associated adverse effects include dermatologic toxicities, diarrhea, decreased appetite, fatigue, and liver dysfunction.

“Because patients end up staying on [FGFR inhibitors] for some time, the more cumulative toxicities…are more relevant,” Shroff stated. “These include nail bed changes that can be quite disabling and painful to our patients, associated skin changes, dry mucous membrane, and stomatitis. There [are some alopecia and ocular adverse effects].…What we’ve learned over time is that [earlier treatment] and using a multidisciplinary team…[are] going to be important.”

Despite the possible adverse effects, BekaiiSaab noted, “[FGFR inhibitors] are quite safe and [toxicities are] relatively manageable for most patients, if not the overwhelming majority of patients.”

There are also several studies evaluating the use of FGFR inhibitors in the first-line treatment of patients with CCA (TABLE8-11). “These frontline studies are very important. I think it is a logical question to see if FGFR inhibitors will be able to replace gemcitabine-cisplatin [chemotherapy],” Shroff noted.

Pemigatinib is being investigated in the first-line treatment of CCA compared with standard of care chemotherapy in the phase 3, randomized, open-label FIGHT-302 study (NCT03656536). Crossover to pemigatinib is permitted upon disease progression from the chemotherapy group.

“We do think this is probably an even better role for patients with FGFR2 fusion to be exposed to these agents sooner rather than later, but that is what the study [is trying to prove],” noted Bekaii-Saab, who is the study’s principal investigator.

Infigratinib is being evaluated in the firstline setting for advanced CCA compared with chemotherapy in the phase 3 PROOF trial (NCT03773302) with planned enrollment of 384 patients with 

 Additionally, futibatinib will be evaluated in the first-line setting against standard chemotherapy for 216 patients with advanced CCA with 

 fusions in the phase 3, randomized, multicenter, open-label FOENIX-CCA3 trial (NCT04093362).

“Here’s the good news: a lot of these studies are looking at first-line [use of FGFR inhibitors],” Bekaii-Saab said. “As we keep uncovering more targets, I think we’re going to fill the landscape of cholangiocarcinoma with primarily agents that are targeted specifically for the cancer and move away from chemotherapy, at least in the first-line treatment.”

However, another challenge associated with the use of FGFR inhibitors is acquired resistance, which may develop by mutation activation or if the signaling pathway is bypassed.1 Point mutations in 

 may lead to clinical resistance of FGFR inhibitors in CCA.

 fusions are early oncogenic drivers, so [they] persist through the course of the patient’s treatment journey. Once [patients] are treated with an FGFR inhibitor, inevitably, they do develop [disease] progression and the presumption is that resistance has developed. There’s some really elegant work that has been done utilizing [circulating tumor DNA] to better understand the mechanism of resistance. What we’ve learned is that resistance is really polyclonal and often involves mutations that change the binding pocket that affects the ability of the FGFR inhibitor to bind, and some of these are what we call gatekeeper mutations,” Shroff said.

There may be differences in mutational resistance due to differing binding specificities of FGFR inhibitors, and there is evidence to suggest polyclonal resistance with multiple acquired 

 mutations in patients treated with infigratinib or pemigatinib in CCA.

 Due to the covalent bond of futibatinib to 

, there may be clinical benefit in CCA with acquired resistance to FGFR inhibitors. Additionally, strategically sequencing FGFR inhibitors may extend the duration of benefit for FGFR inhibitor use.

“There’s more to be done since we’re at the tip of the iceberg of trying to understand mechanisms of resistance with these agents,” Bekaii-Saab said. Given the challenges with FGFR inhibitor use, the future of CCA treatment is still extremely promising.

“I would imagine in the next 5 to 10 years, we’re going to continue with this positive upward trajectory and have more drugs available,” Shroff said. “I firmly believe we will move the needle forward in terms of median overall survival for this disease in the advanced setting. I think we will figure out how to integrate some of these novel targeted therapies and [potentially] immunotherapy into more localized disease and perioperative approaches…. At the end of the day, surgery is our curative treatment, and anything we can do to build on outcomes for patients [who] can undergo surgery is obviously very important.”

1. Wang J, Xing X, Li Q, et al. Targeting the FGFR signaling pathway in cholangiocarcinoma: promise or delusion? 

 2020;12:1758835920940948. doi:10.1177/1758835920940948 

2. Silverman IM, Hollebecque A, Friboulet L, et al. Clinicogenomic analysis of FGFR2-rearranged cholangiocarcinoma identifies correlates of response and mechanisms of resistance to pemigatinib.

. 2021;11(2):326-339. doi:10.1158/2159-8290.CD-20-0766 

3. Abou-Alfa GK, Bibeau K, Schultz N, et al. Effect of FGFR2 alterations on survival in patients receiving systemic chemotherapy for intrahepatic cholangiocarcinoma. 

l. 2021;39(suppl 3):303. doi:10.1200/ JCO.2021.39.3_suppl.303 

4. FDA grants accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion. FDA. Updated April 20, 2020. Accessed March 5, 2021. https://bit.ly/2QomFdh 

5. Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. 

. 2020;21(5):671-684. doi:10.1016/S1470-2045(20)30109-1 

6. Javle MM, Roychowdhury S, Kelley RK, et al. Final results from a phase II study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement. 

. 2021;39(suppl 3):265. doi:10.1200/JCO.2021.39.3_suppl.265

7. Goyal L, Meric-Bernstam F, Hollebecque A, et al. FOENIX-CCA2: A phase II, open-label, multicenter study of futibatinib in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 gene fusions or other rearrangements. 

. 2020;38(suppl 15):108. doi:10.1200/ JCO.2020.38.15_suppl.108 

8. Goyal L, Shi L, Liu LY, et al. TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma. 

. 2019;9(8):1064-1079. doi:10.1158/2159-8290.CD-19-0182 

9. Bekaii-Saab TS, Valle JW, Cutsem EV, et al. FIGHT-302: phase III study of first-line (1L) pemigatinib (PEM) versus gemcitabine (GEM) plus cisplatin (CIS) for cholangiocarcinoma (CCA) with FGFR2 fusions or rearrangements. 

. 2020;38(suppl 4):TPS592. doi:10.1200/JCO.2020.38.4_suppl.TPS592 

10. Javle MM, Borbath I, Clarke SJ, et al. Infigratinib versus gemcitabine plus cisplatin multicenter, open-label, randomized, phase 3 study in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/ translocations: the PROOF trial. 

. 2019;37(suppl 15):TPS4155. doi:10.1200/JCO.2019.37.15_suppl.TPS4155 

11. Borad MJ, Bridgewater JA, Morizane C, et al. A phase III study of futibatinib (TAS-120) versus gemcitabine-cisplatin (gem-cis) chemotherapy as first-line (1L) treatment for patients (pts) with advanced (adv) cholangiocarcinomva (CCA) harboring fibroblast growth factor receptor 2 (FGFR2) gene rearrangements (FOENIX-CCA3). 

. 2020;38:(suppl 4):TPS600. doi:10.1200/JCO.2020.38.4_suppl.TPS600

Although chemotherapy is the mainstay of systemic treatment for advanced cholangiocarcinoma, there are limited treatment options when the disease progresses

FGFR Inhibitors Make Inroads in Cholangiocarcinoma

Over the past several years, the oncology community has witnessed a significant improvement in identifying genetic mutations associated with increased risk of breast malignancies.

 As the understanding of genetic risk factors in breast cancer continues to grow, professional organizations have sought to provide specific recommendations for genetic testing that would prevent overtesting yet still diagnose as many mutations as possible in patients.

“In general, the gold standard [for guidelines] is clinical utility,” said Susan M. Domchek, MD, the Basser Professor in Oncology at Penn Medicine in Philadelphia, executive director of the Basser Center for 

, and director of MacDonald Women’s Cancer Risk Evaluation Center. “We’re all looking at the same data, and it just comes down to perspective for how you interpret those data.”

Currently, controversy surrounds guideline recommendations for eligibility in genetic testing. The US Preventive Services Task Force and the National Comprehensive Cancer Network (NCCN) guidelines recommend genetic testing for patients with breast cancer and a family history associated with germline 

1/2 mutations or who have a personal history with an increased risk of 

Utilizing testing criteria recommended by the NCCN may not identify a small number of individuals who have no family history but carry pathogenic variants of high-risk breast cancer genes.

“The guidelines from the NCCN focus on the likelihood of finding genes where we have specific information [on] how to use that and how helpful it is to patients, for instance, [with] BRCA and other [high-penetrance] gene mutations,” said Domchek.

Conversely, the American Society of Breast Surgeons (ASBrS) recommends genetic testing for all patients with breast cancer.

 However, the paradigm shift from genetic testing in individuals with a family history to the testing of all patients with breast cancer, as recommended by ASBrS, may lead to unnecessary testing and the potential for harm.

 The optimal model for genetic testing in patients with breast cancer has not yet been identified, though some strategies have been proposed.

As the understanding of genetic risk factors in breast cancer continues to grow, professional organizations have sought to provide specific recommendations for genetic testing that would prevent overtesting yet still diagnose as many mutations as possible in patients.

Thao K . Huynh, PharmD , BCOP | Authors

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