Frontline Tiragolumab/Atezolizumab Combo Misses PFS End Point in PD-L1–High Metastatic NSCLC

The anti-TIGIT immunotherapy tiragolumab in combination with atezolizumab (Tecentriq) did not improve progression-free survival (PFS) over atezolizumab alone in the first-line treatment of patients with PD-L1–high locally advanced or metastatic non–small cell lung cancer (NSCLC), missing the co-primary end point of the phase 3 SKYSCRAPER-01 trial (NCT04294810).¹

Data from this first analysis indicated that the combination resulted in a numerical improvement in PFS and the other co-primary end point of the trial, overall survival (OS), vs the monotherapy in this population. However, OS data remain immature at this time point.

The addition of tiragolumab to atezolizumab did not result in new safety signals, and the regimen was found to be well tolerated.

The study is slated to continue until the next planned analysis, with additional analyses of these results ongoing, according to Roche. The findings from the trial will be shared at an upcoming medical conference.

“While these results are not what we hoped for in our first analysis, we look forward to seeing mature OS for this study to determine next steps,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Roche, stated in a press release. “We continue to believe that TIGIT may have a role in cancer treatment, and we will share additional results from our tiragolumab programme as they emerge.”

Tiragolumab, which is an investigational immune checkpoint inhibitor with an intact Fc region, was designed to selectively bind to TIGIT, which is known to suppress the immune response to cancer. Preclinical data have suggested that when this agent is combined with other immunotherapies like atezolizumab, it could potentially serve as an immune amplifier. Investigators hypothesized that dual blockade with these 2 drugs could overcome immune suppression and restore response.

The global, randomized, double-blinded, phase 3 SKYSCRAPER-01 trial enrolled patients with histologically or cytologically confirmed locally advanced or recurrent NSCLC who were not eligible for curative surgery and/or definitive radiotherapy with or without chemoradiation.²

Patients were required to be at least 18 years of age, have measurable disease per RECIST v1.1 criteria, high PD-L1 expression on tumor tissue, an ECOG performance status of 0 or 1, and acceptable hematologic and end-organ function.

If they had known EGFR or ALK alterations, active or a history of autoimmune disease or immune deficiency, malignancies other than NSCLC within 5 years, or symptomatic, untreated, or actively progressing central nervous system metastases, they were excluded. Patients were not eligible for enrollment if they received an investigational drug within 28 days before study treatment was started, prior treatment with CD137 agonists or immune checkpoint blockade therapies, or systemic immunostimulatory agents within 4 weeks of study treatment.

A total of 534 patients were enrolled to the trial and were randomized 1:1 to receive intravenous (IV) atezolizumab at 1200 mg followed by tiragolumab at 600 mg every 3 weeks on day 1 of each 21-day cycle, or atezolizumab alone. Treatment was given until disease progression, loss of clinical benefit, or intolerable toxicity.

The co-primary end points of the trial are investigator-assessed PFS and OS in the primary analysis set.

Secondary end points include investigator-assessed PFS and OS in the secondary analysis set, and investigator-assessed objective response rate, duration of response, and PFS rates at 6 months and 12 months. Other end points include OS rates at 12 months and 24 months, time to confirmed deterioration, and safety, among others.

The combination of tiragolumab, atezolizumab, carboplatin, and etoposide was evaluated in patients with extensive-stage small cell lung cancer (SCLC) as part of the phase 3 SKYSCRAPER-02 trial (NCT04256421). In March 2022, data from the interim analysis indicated that the addition of tiragolumab did not result in a significant improvement in PFS over atezolizumab plus chemotherapy alone, missing the co-primary end point of the trial.³

Moreover, the co-primary end point of OS was also not met at the time of the analysis and was determined to be unlikely to reach statistical significance at the planned final analysis. Again, however, the tiragolumab regimen was found to have acceptable tolerability in these patients.

In January 2021, the FDA granted a breakthrough therapy designation to tiragolumab for use in combination with atezolizumab in the first-line treatment of patients with metastatic NSCLC whose tumors are PD-L1 high and who do not harbor EGFR or ALK aberrations.⁴

The decision was supported by findings from the phase 2 CITYSCAPE trial (NCT03563716). At a median follow-up of 30.4 months, the doublet resulted in a median PFS of 5.6 months (95% CI, 4.2-10.4) per investigator assessment in treatment-naïve patients with stage IV NSCLC who had EGFR or ALK wild-type NSCLC vs 3.9 months (95% CI, 2.7-4.5) with atezolizumab alone. The median OS in the investigative arm was 23.2 months (95% CI, 14.1-31.5) vs 14.5 months (95% CI, 9.6-20.4) in the control arm.

At the time of the primary analysis of the trial, which had a median follow-up of 5.9 months, the doublet resulted in a clinically meaningful improvement in ORR and PFS in the intent-to-treat population vs atezolizumab monotherapy.

Additional data presented during the 2021 ESMO Immuno-Oncology Congress showed that the median PFS among those with a PD-L1 TPS of more than 50% was 16.6 months (95% CI, 5.5-22.3) with the doublet vs 4.1 months (95% CI, 2.1-6.8) with the monotherapy; the 12-month PFS rates were 51.0% and 21.8%, respectively.⁵ The median PFS among those with a PD-L1 TPS of 1% to 49% was 4.0 months (95% CI, 1.6-5.6) vs 3.6 months (95% CI, 1.4-5.5) in the investigative and control arms, respectively; the 12-month PFS rates in this subset were 24.9% and 20.5%, respectively.

In the ITT population, the 12-month OS rates with the doublet and the monotherapy were 66.1% and 58.0%, respectively; the 24-month OS rates were 47.2% and 34.3%, respectively.

The median OS in the subset of patients with a PD-L1 TPS of more than 50% was not evaluable (NE; 95% CI, 30.3-NE) with the combination vs 12.8 months (95% CI, 4.7-24.2) with atezolizumab monotherapy; the 12- and 24-month OS rates were 81.9% and 56.1%, respectively, and 78.2% and 33.7%, respectively.

Among the subset of patients with a PD-L1 TPS ranging from 1% to 49%, the median OS was 13.3 months (95% CI, 8.0-20.7) with the doublet vs 14.5 months (95% CI, 8.3-25.6) with atezolizumab alone; the OS rates at 12 months were 54.4% and 59.5%, respectively, and the 24-month OS rates were 24.5% and 35.0%, respectively.

SKYSCRAPER-01 was designed to confirm the results yielded in CITYSCAPE.

According to Roche, the tiragolumab program will continue to examine avenues to build on the benefit derived with atezolizumab.

References

1. Roche reports interim results for phase III SKYSCRAPER-01 study in PD-L1–high metastatic non-small cell lung cancer. News release. Roche; May 11, 2022. Accessed May 11, 2022. https://bit.ly/3yuFijz
2. A study of tiragolumab in combination with atezolizumab compared with placebo in combination with atezolizumab in patients with previously untreated locally advanced unresectable or metastatic PD-L1-selected non-small cell lung cancer (SKYSCRAPER-01). ClinicalTrials.gov. Updated December 7, 2021. Accessed May 11, 2022. https://clinicaltrials.gov/ct2/show/NCT04294810
3. Ad hoc announcement pursuant to Art. 53 LR Roche provides update on phase III SKYSCRAPER-02 study in extensive-stage small cell lung cancer. News release. Roche; March 30, 2022. Accessed May 11, 2022. https://bit.ly/36HFr7N
4. 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 May 11, 2022. http://bit.ly/2LoNrj2
5. Cho BC, Rodriguez-Abreu D, Hussein M, et al. Updated analysis and patient-reported outcomes (PROs) from CITYSCAPE: A randomised, double-blind, phase II study of the anti-TIGIT antibody tiragolumab + atezolizumab (TA) versus placebo + atezolizumab (PA) as first-line treatment for PD-L1+ NSCLC. Ann Oncol. 2021;32(suppl 17):S1428. doi:10.1016/j.annonc.2021.10.217