Tiragolumab/Atezolizumab Shows Early First-in-Human Efficacy in Frontline PD-L1+ NSCLC | OncLive

Tiragolumab/Atezolizumab Shows Early First-in-Human Efficacy in Frontline PD-L1+ NSCLC

June 24, 2020

Tiragolumab in combination with atezolizumab (Tecentriq) demonstrated early clinical activity and was found to be well tolerated in patients with advanced solid tumors, including those with metastatic non–small cell lung cancer who were PD-L1 positive and had not received prior checkpoint inhibition.

Tiragolumab in combination with atezolizumab (Tecentriq) demonstrated early clinical activity and was found to be well tolerated in patients with advanced solid tumors, including those with metastatic non–small cell lung cancer (NSCLC) who were PD-L1 positive and had not received prior checkpoint inhibition, according to first-in-human results of the phase 1 Study GO30103 (NCT02794571) that were presented during the 2020 AACR Virtual Annual Meeting II.1

Results showed that in this expansion subset of patients who received tiragolumab in combination with atezolizumab (n = 13), the objective response rate (ORR) was 46% and the disease control rate was 85%. Additionally, no dose-limiting toxicities (DLTs) occurred at the varying dose levels explored in the dose-escalation phase of the trial.

No objective responses were observed with tiragolumab as monotherapy, yet several patients did experience tumor shrinkage. Notably, most patients had tumors known to be unresponsive to immunotherapy, had PD-L1–negative disease, or were heavily pretreated, explained lead study author Johanna C. Bendell, MD, a medical oncologist at Sarah Cannon Research Institute, in a presentation during the meeting.

“Tiragolumab was well tolerated as both a single agent and in combination with atezolizumab. No dose-limiting toxicities were seen, and the safety profile with atezolizumab appears similar to that of other checkpoint inhibitors,” said Bendell. “No objective responses were seen with single-agent tiragolumab, although most of the patients had tumor types that do not typically respond to immunotherapy. We did [see] responses in the phase 1b [stage], mostly in [those with] immunotherapy-naïve PD-L1–positive tumors.”

TIGIT is a novel inhibitory receptor that is expressed on multiple immune cells, including T cells and natural killer (NK) cells; it inhibits T cells and NK cells by binding to the poliovirus receptor (PVR), downregulates antigen-presenting cells, and binds to and blocks CD226. TIGIT expression is also found to correlate with PD-1, especially in tumor-infiltrating cells, and it is often co-expressed on the same cell.

Therefore, investigators hypothesized that TIGIT-directed antibodies, which prevent TIGIT from binding, may restore antitumor response and enhance PD-L1 antibody therapy. Preclinical data have demonstrated that the combination of anti-TIGIT and anti–PD-L1 synergistically improves tumor control and prolongs survival.

Tiragolumab is a fully human IgG1/kappa TIGIT monoclonal antibody with an intact Fc region that blocks TIGIT from binding to its PVR ligand and to the co-activating receptor CD226.

In the phase 1 Study GO30103, investigators evaluated tiragolumab as a single agent (phase 1a) and in combination with atezolizumab (phase 1b) in patients with advanced solid tumors. The trial included a dose-escalation stage (stage 1) and a dose-expansion stage at the recommended phase 2 dose (RP2D; stage 2).

To be eligible for enrollment, patients must have advanced solid tumors for whom standard treatment is not available or is ineffective. They also needed be 18 years or older, have an ECOG performance status of 0 or 1, and measurable disease per RECIST v1.1 criteria. For the expansion cohorts, patients must have had PD-L1–positive disease and had not received previous treatment with checkpoint inhibitors.

Those who received prior anti-TIGIT therapy, received anticancer therapy within 3 weeks or palliative radiation within 2 weeks of study treatment, discontinued prior immunotherapy due to immune-mediated grade 3 or higher adverse events (AEs), had prior active or untreated central nervous system metastases, and a history of autoimmune system were ineligible for enrollment.

The primary end point of the phase 1a portion of the study was to determine the preliminary safety, tolerability, and RP2D of tiragolumab. The primary end point was the same in the phase 2b stage of the trial, but of tiragolumab in combination with atezolizumab. Secondary end points of the trial included pharmacokinetics as well as the preliminary antitumor activity of tiragolumab alone and with atezolizumab.

In the phase 1a dose-escalation phase, tiragolumab was administered at a fixed-dose delivered intravenously (IV) every 3 weeks, beginning at 2 mg and escalating to 8 mg, 30 mg, 100 mg, 400 mg, 600 mg, and 1200 mg. There was a dose-limiting toxicity (DLT) window of 21 days, and backfill enrollment was permitted in cleared dose levels. The 400-mg, 600-mg, and 1200-mg doses were evaluated in the dose-expansion phase of the trial. Patients who progressed on single-agent tiragolumab were permitted to cross over and receive the combination.

In the phase 1b dose-escalation phase with the combination, the same increasing doses of tiragolumab were given every 3 weeks in combination with a fixed dose of atezolizumab at 1200 mg IV, also every 3 weeks. In the dose-expansion phase, the 400- and 600-mg doses of tiragolumab were evaluated in the dose-expansion phase in patients with NSCLC as well as other expansion cohorts of solid tumors, Bendell explained.

Regarding baseline characteristics, the median age was 59.5 years (range, 40-77) and 54.0 years (range, 25-81) in the phase 1a (n = 24) and phase 1b groups (n = 49), respectively. Overall, 45.5% of patients were male, and 72.5% of patients had an ECOG performance status of 1. Most patients were white (62%) and 39.5% of patients had previously received 4 or more lines of therapy.

Dose escalation has been completed for each dose level in the phase 1a and phase 1b parts of the trial. In the phase 1a group, 0 patients were still on treatment compared with 5 patients on phase 1b who were continuing with the combination.

Of the 100% of patients who received single-agent tiragolumab and discontinued treatment, 42% discontinued treatment because of disease progression, 8% withdrew, and 50% had crossed over to receive the combination in the phase 1b stage.

For those who were on the combination, 76% of patients experienced disease progression, and thus, discontinued treatment, 12% of patients withdrew, and 2% of patients were lost to follow-up.

Regarding safety, no DLTs were observed across all dose levels in both phases. Any-cause AEs were reported in 100% and 94% of patients on single-agent versus combination therapy; however, 25% of patients on tiragolumab alone experienced a grade 3 to 5 AE compared with 57% of those on combination treatment. Serious AEs were reported in 25% and 53% of patients, respectively, and AEs that led to study drug interruption occurred in 17% and 25% of patients, respectively. One patient on the combination arm had an AE that led to treatment withdrawal.

The most common AEs occurring in 10% or more of the patients who received tiragolumab alone that were found to be related to treatment were mostly grade 1/2, including fatigue, pruritis, arthralgia, and myalgia. In the combination group, treatment-related AEs included fatigue, pruritis, arthralgia, nausea, and rash. All-cause grade 3 or higher AEs included anemia, constipation, pyrexia, hyponatremia, arthralgia, AST increase, hypophosphatemia, and malignant progression (grade 5).

Immune-mediated AEs occurred in 17% and 59% of patients on single-agent tiragolumab and tiragolumab in combination with atezolizumab, respectively, 4% of which on the combination arm were grade 3 or higher.

“Immune-related AEs were seen, but their incidence was not out of proportion to events seen with atezolizumab alone,” Bendell said.

Immune-mediated AEs included infusion-related reaction (8% with monotherapy vs 8% with combination), rash (8% vs 29%, respectively), hepatitis (4% vs 20%), pancreatitis (4% vs 2%), hyperthyroidism (0% vs 8%), hypothyroidism (0% vs 6%), and anemia (0% vs 2%). No grade 4 immune-mediated AEs were reported with tiragolumab and/or atezolizumab.

Moreover, Bendell noted that tiragolumab exposure increased with dose, and the pharmacokinetics of the TIGIT antibody were not found to be altered when used in combination with atezolizumab. Complete and sustained occupancy of peripheral TIGIT receptors on CD+ T cells and NK cells were observed at doses of 30 mg or higher of tiragolumab when administered as monotherapy.

Based on these data, the RP2D was chosen as 600 mg of tiragolumab given every 3 weeks. Bendell noted that clinical activity with tiragolumab occurred at 400 mg to 600 mg, as determined by partial responses in the combination arm. Additional expansion cohorts were launched with tiragolumab in combination with atezolizumab in patients with PD-L1–positive, checkpoint inhibitor–naïve indications, including metastatic NSCLC.

Due to the preliminary clinical activity and safety in the phase 1 trial, investigators are now exploring the combination in the phase 2 CITYSCAPE trial in patients with NSCLC, early results of which were presented at the 2020 ASCO Virtual Scientific Program.2

In the 2-arm, blinded trial, patients with chemotherapy-naïve, locally advanced or metastatic NSCLC were randomized 1:1 to received IV infusions of atezolizumab at 1200 mg plus either IV tiragolumab at 600 mg or matched placebo in 3-week cycles until progressive disease or loss of clinical benefit. Patients were stratified by PD-L1 status (tumor proportion score [TPS] 50% or higher or TPS 1% to 49%), histology, and tobacco history. Coprimary end points of the trial were investigator-assessed ORR and progression-free survival (PFS), with secondary outcome measures that included duration of response, OS, patient-reported outcomes, and safety.

At the primary analysis, tiragolumab plus atezolizumab administered every 3 weeks resulted in a 43% reduction in the risk of disease progression or death compared with atezolizumab and placebo in the intent-to-treat population (stratified HR, 0.57; 95% CI, 0.37-0.90). With an additional 6 months of follow-up, improvement in PFS was maintained with medians of 5.6 months versus 3.9 months, respectively (stratified HR, 0.58; 95% CI, 0.38-0.89).

At the primary analysis, the ORR in the tiragolumab arm was 31% versus 16% with placebo; the updated confirmed ORR in both groups was 37% and 21%, respectively.

In an exploratory analysis of patients with high PD-L1 expression, or those with a TPS above 50% (n = 58), a 70% reduction in the risk of disease progression or death was reported with tiragolumab versus placebo (stratified HR, 0.30; 95% CI, 0.15-0.61). The median PFS for patients with a high PD-L1 expression was not evaluable with tiragolumab plus atezolizumab versus 4.1 months with atezolizumab alone; the corresponding ORRs were 66% and 24%, respectively.

The ongoing phase 3 SKYSCRAPER-01 trial (NCT04294810) is examining tiragolumab plus atezolizumab versus placebo/atezolizumab in patients with previously untreated locally advanced unresectable or metastatic PD-L1–selected NSCLC. Additionally, the ongoing phase 3 SKYSCRAPER-02 study (NCT04256421), another phase 3 trial, is exploring atezolizumab plus carboplatin or etoposide with or without tiragolumab in patients with untreated extensive-stage small cell lung cancer.

References

  1. Bendell JC, Bedard P, Bang Y-J, et al. CT302 - Phase Ia/Ib dose-escalation study of the anti-TIGIT antibody tiragolumab as a single agent and in combination with atezolizumab in patients with advanced solid tumors. Presented at: 2020 AACR Virtual Annual Meeting; June 22-24, 2020; Virtual. Abstract CT302.
  2. 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). J Clin Oncol. 2020;38(suppl 15):9503. doi:10.1200/JCO.2020.38.15_suppl.9503

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