Adding the anti-TIGIT agent tiragolumab to atezolizumab-chemotherapy does not extend the survival of patients with extensive stage small-cell lung cancer

Results of the phase III SKYSCRAPER-02 trial failed to show a survival benefit from the addition of the anti-TIGIT agent tiragolumab to atezolizumab plus chemotherapy in the treatment of newly diagnosed patients with extensive-stage small cell lung cancer (ES-SCLC). As such, these data confirm atezolizumab plus chemotherapy as a standard of care for first-line treatment for these patients. Nevertheless, the tiragolumab regimen was well-tolerated and other studies are ongoing to assess the potential of tiragolumab in the treatment of patients with non–small cell lung, esophageal and cervical cancer.

Introduction

Following the publication of the CASPIAN and IMpower133 trials, the addition of an anti–PD-L1 therapy to chemotherapy has become the standard of care in the first line treatment of patients with ES SCLC. In fact, these trials showed that respectively, adding durvalumab or atezolizumab to platinum-etoposide significantly improves the overall survival (OS) of ES-SCLC patients without adding significant toxicity. TIGIT is a new immune checkpoint that is present in many cancers. Its expression is highly correlated with PD-L1 expression and targeting this immune checkpoint may synergize with other immunotherapies.

Study design

The double-blind SKYSCRAPER-02 trial randomly assigned 490 patients with untreated ES-SCLC to receive four 21-day induction cycles of atezolizumab plus chemotherapy (consisting of carboplatin and etoposide), with or without the anti-TIGIT agent tiragolumab. After this induction phase, maintenance therapy with atezolizumab plus either placebo or tiragolumab was continued every 3 weeks until disease progression. Crossover was not allowed in this study. The co-primary endpoints were investigator-assessed OS and progression-free survival (PFS) in the primary analysis set, which consisted of all randomly assigned patients without presence or history of brain metastases at baseline. Secondary endpoints included PFS and OS in the entire randomly assigned population, objective response rate, duration of response, and safety.

Results

About half of the patients in the study was older than 65 years, and almost all patients were current (~30%) or previous (~63%) smokers. Furthermore, two thirds of patients had an ECOG performance status of 1 and 40% had a lactate dehydrogenase level equal or below the upper limit of normal. Brain metastases were present in about one fifth of patients, whereas a third of patients had liver metastases at baseline.

The addition of tiragolumab to atezolizumab-chemotherapy did not induce a PFS benefit with a median of 5.4 and 5.6 months for the experimental and control arm, respectively (HR[95%CI]: 1.11[0.89-1.38]; p= 0.3504). Similarly, also the OS did not differ between both arms, with a median OS of 13.6 in both treatment arms (HR[95%CI]: 1.04[0.79-1.36]; p= 0.7963). A further subgroup analysis did not reveal a subgroup that selectively benefited from the addition of tiragolumab.

The safety profile observed with the triplet regimen in SKYSCRAPER-2 was similar to that of atezolizumab plus chemotherapy and was in line with previous reports. No new safety signals were observed.

Conclusions

The addition of the anti-TIGIT agent tiragolumab to atezolizumab plus chemotherapy in the first line treatment of patients with ES-SCLC did not lead to a better PFS or OS. SKYSCRAPER-02 study will continue to complete the planned primary OS analysis and biomarker analyses are ongoing to define subgroups that may benefit selectively from the addition of anti-TIGIT therapy. Despite being negative, the trial did learn that atezolizumab plus chemotherapy is probably appropriate and safe to use in patients with asymptomatic brain metastases, a patient group that was excluded from the prior IMpower133 trial.

Reference

Rudin C, et al. SKYSCRAPER-02: Primary results of a phase III, randomized, double-blind, placebo-controlled study of atezolizumab (atezo) + carboplatin + etoposide (CE) with or without tiragolumab (tira) in patients (pts) with untreated extensive-stage small cell lung cancer (ES-SCLC). Presented at ASCO 2022; Abstract LBA8507.