CE / CME
Pharmacists: 1.00 contact hour (0.1 CEUs)
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Nurses: 1.00 Nursing contact hour
Released: April 27, 2022
Expiration: April 26, 2023
Diwakar Davar, MD:
Tiragolumab (MTIG7192A) is a fully humanized IgG1 Fc‑active anti‑TIGIT mAb that blocks the interaction between PVR and TIGIT. Tiragolumab can prevent TIGIT on T‑cells or NK cells from interacting with PVR‑expressing tumor cells, thus restoring antitumor immune activity.14 In preclinical models, the combination of TIGIT and PD‑L1 blockade with a mAb acted synergistically to decrease tumor size and improve survival, effects that were dependent on the presence of T‑cells.15 Depletion of CD8 T‑cells resulted in loss of tumor control.
Diwakar Davar, MD:
The efficacy of the anti‑TIGIT inhibitor tiragolumab in advanced solid tumors was first evaluated by Johanna Bendell and colleagues in the GO30103 study, which was reported at AACR in 2020 (NCT02794571).16 This was the first in-human phase I study of tiragolumab, which was given as a single agent in the phase Ia portion and in combination with the anti–PD‑L1 inhibitor atezolizumab in the phase Ib portion in patients with advanced solid tumors. Stage I consisted of dose escalation, and stage II consisted of dose expansion at the recommended phase II dose.
In the phase Ia portion, 24 patients were enrolled at doses from 2 mg to 1200 mg administered as a fixed dose every 3 weeks. These patients were extensively pretreated. No dose‑limiting toxicities were observed, and there were no objective responses noted.
In the phase Ib portion, 49 patients received tiragolumab at 2 mg to 1200 mg in combination with atezolizumab, given at 1200 mg every 3 weeks. Backfill enrollment was permitted as dose levels were cleared in the phase Ia and Ib. Patients who had disease progression in the phase Ia portion could cross over to phase Ib. Based on the confirmed responses observed in the phase Ib portion, expansion cohorts were initiated with tiragolumab and atezolizumab in multiple indications, including cancer immunotherapy-naive PD‑L1–positive NSCLC.
Tiragolumab exposure increased with dose, and the pharmacokinetics of tiragolumab were not altered in combination with atezolizumab. In conclusion, GO30103 selected 600 mg every 3 weeks as the recommended phase II dose of tiragolumab, based on the observation of complete and sustained peripheral receptor occupancy that occurred at doses >30 mg, as well as the phase Ib clinical activity that was observed at doses of ≥400 mg.
Diwakar Davar, MD:
As stated, expansion cohorts in immunotherapy-naive patients with PD-L1-positive cancer were initiated, which included enrollment of 13 patients with metastatic NSCLC. This cohort had an ORR of 46%, composed of 2 complete and 4 partial responses, and a disease control rate of 85% (11/13).
Diwakar Davar, MD:
Overall, treatment with tiragolumab with or without atezolizumab was relatively well tolerated. Among the 24 patients treated in the phase Ia portion, 4 (17%) patients had immune‑mediated adverse events, none of which were grade ≥3. In the phase Ib portion with the combination treatment, 29 (59%) had any‑grade irAEs, of which 2 (4%) were grade ≥3. Again, no dose-limiting toxicities were observed.
Jyoti D. Patel, MD:
The promising phase I response rate and tolerable safety of the combination of tiragolumab and atezolizumab helped lead to the CITYSCAPE trial, which is a phase II study of tiragolumab and atezolizumab vs placebo and atezolizumab in patients with treatment‑naive, PD‑L1–positive NSCLC. This trial was initially presented by Johnson and colleagues at the American Society of Clinical Oncology annual meeting in 2020, with updates presented by Cho and colleagues at the European Society for Medical Oncology Immuno-Oncology Congress in 2021.14,17
CITYSCAPE is a randomized, double‑blind phase II trial that enrolled 135 patients with no prior therapy who were EGFR and ALK wild‑type and had ≥1% PD‑L1 expression in their tumor by 22C3 immunohistochemistry. Patients were randomized to receive atezolizumab with either tiragolumab or placebo every 3 weeks until progression or loss of clinical benefit. Patients were stratified by PD‑L1 scores of 1% to 49% vs ≥50%, by squamous vs nonsquamous histology, and by tobacco use. The primary endpoints were response rate and PFS.
Jyoti D. Patel, MD:
In the full ITT population, the response rate was 37% with the combination vs 21% in the placebo arm.14 However, the effect of tiragolumab was most marked in the patients with high PD‑L1 expression, with response rates of 66% with tiragolumab vs 24% with placebo. In the patients with PD-L1 expression of 1% to 49%, the response rates were very similar between treatment arms, 16% and 18%, respectively.
One should note that the patients who received atezolizumab and placebo in this study showed lower than expected response rates, especially those patients with PD‑L1 tumor proportion scores of ≥50%. We would expect approximately double these rates in a high PD‑L1 population receiving pembrolizumab or ICI monotherapy.
Overall, these are small numbers of patients, but we can clearly see a difference between combination vs monotherapy in this study, particularly in the high PD-L1 subgroup.
Jyoti D. Patel, MD:
With a median follow-up of 30.4 months, we can see a marked difference between treatment groups in PFS among the 58 patients with high PD‑L1 scores. Patients receiving the combination had a median PFS of almost fourfold better than those who received atezolizumab alone, 16.6 months vs 4.1 months.17 In patients with PD‑L1 scores of 1% to 49%, the PFS curves are quite similar, with median PFS of 3.6-4.0 months, reflecting the similar response rates.
Jyoti D. Patel, MD:
OS results show a similar pattern, with an improvement in OS with the addition of tiragolumab in patients with high PD-L1 scores. Median OS was not estimable in the combination arm vs 12.8 months with placebo.17 In patients with lower PD-L1 scores, again the survival curves were very similar.
Jyoti D. Patel, MD:
Patients on the combination therapy ended up receiving more treatment, consistent with the prolongation in PFS, so perhaps it is not surprising that incidence of grade 3/4 toxicities was mildly increased with dual therapy, approximately 52% vs 40%.17 Similarly, serious adverse events (AEs) occurred in 52% in the combination arm vs 41% in the placebo arm. Treatment-related AEs were quite similar between groups. Immune‑mediated AEs were a bit higher in the combination arm, affecting 76% of patients vs 47% in the placebo arm. AEs leading to dose modification or interruption occurred in 49% of the dual therapy arm vs 35% of the placebo and monotherapy arm, but AEs leading to discontinuation were similar between the 2 arms.
Jyoti D. Patel, MD:
The CITYSCAPE trial results were certainly exciting, and the combination of tiragolumab and atezolizumab is now being investigated in an ongoing phase III study, the SKYSCRAPER‑01 trial, as frontline therapy for patients with high PD‑L1 ≥50% advanced NSCLC (NCT04294810). This combination currently has the FDA’s breakthrough therapy status. If approved, it would be a significant paradigm change and the first new immunotherapy combination approval since anti–PD‑1/anti–CTLA-4 combination.
Jyoti D. Patel, MD:
Vibostolimab is another anti‑TIGIT antibody investigated in a first-in-human phase I trial. Similar to tiragolumab, it has a fully human IgG1 backbone. Patients with advanced or metastatic NSCLC, either treatment naive or who progressed on prior therapy but had no prior anti–PD-1 or anti–PD-L1 therapy, received vibostolimab and pembrolizumab every 3 weeks for up to 35 cycles. This phase I trial with a part B expansion cohort enrolled 41 patients. The primary endpoints are safety and tolerability, with secondary endpoints of response rate, duration of response, and PFS.18
Jyoti D. Patel, MD:
Looking at the patient demographics, nearly one quarter of patients had third-line or greater therapy. Of the 61% of patients with available samples to determine PD‑L1 status, 29% had TPS <1% and 32% had TPS ≥1%.
Jyoti D. Patel, MD:
The safety data in this trial are quite similar to those seen with tiragolumab plus atezolizumab. Grade 3 or higher treatment-related AEs occurred in 15% of patients, and there were no high-grade serious AEs. The discontinuation rate is somewhat lower compared with CITYSCAPE, with all-cause AEs leading to discontinuation in 7%, but recall that this is a phase I trial, so the patient population may have been a bit more selective.
Jyoti D. Patel, MD:
Several patients in this study, including some with TPS <1%, had significant tumor reduction from baseline. Some of those patients had durable and ongoing responses, up to almost 2 years in one patient.
Jyoti D. Patel, MD:
Median PFS for these 41 patients was 5.4 months. Median PFS was 8.4 months for the 13 patients with TPS ≥1% and 4.1 months for the 12 patients with TPS <1%. Again, these data are incomplete because of a lack of tumor sample for many of the patients.
The investigators concluded that vibostolimab given in combination with pembrolizumab was well tolerated with no new safety signals. These preliminary results seem to support ongoing clinical investigation of this combination in patients with NSCLC.
Jyoti D. Patel, MD:
Aside from lung cancer, trials of anti-TIGIT therapies are ongoing in other solid tumors, such as the SKYSCRAPER-07 trial, which is evaluating atezolizumab with or without tiragolumab vs placebo in patients with unresectable esophageal squamous cell carcinoma following chemoradiation. The coprimary endpoints will be PFS in those receiving atezolizumab plus tiragolumab vs placebo and OS in those receiving atezolizumab pus tiragolumab vs placebo and atezolizumab vs placebo.
Jyoti D. Patel, MD:
SKYSCRAPER-02 looked at the addition of tiragolumab to carboplatin and etoposide in untreated extensive-stage small-cell lung cancer without symptomatic or actively progressing central nervous system metastases. At present, this study did not meet its coprimary endpoint of PFS. The full results of this study are yet to be presented.
Jyoti D. Patel, MD:
These early studies are showing intriguing activity of mAbs targeting TIGIT, and several additional compounds are now being investigated in clinical trials, primarily phase I/II. There are some differences in Fc structure across these compounds, and we can look forward to seeing data on these agents in the near future.
Jyoti D. Patel, MD:
Currently, most studies are evaluating anti-TIGIT therapy in advanced solid tumors. Of particular interest are the phase III trials in both non‑small-cell and small-cell populations, primarily in the treatment‑naive setting. I think for many of us, key clinical questions are how anti-TIGIT therapies will be differentiated from other immunotherapy combinations and which patient populations are likely to see maximum benefit from these drugs.
Jyoti D. Patel, MD:
In conclusion, TIGIT is an emerging immune checkpoint target with numerous antibodies under investigation. Currently, the combination of tiragolumab plus atezolizumab has shown promise in the first-line setting for NSCLC with high PD-L1 expression.
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