The reduced efficacy compared to the first-line standard of care led to the termination of the SKYSCRAPER-06 study
First-line combination of tiragolumab, a monoclonal antibody that blocks TIGIT from binding to its ligand, plus atezolizumab and chemotherapy failed to improve progression-free survival (PFS) and overall survival (OS) compared to standard therapy in patients with locally advanced unresectable or metastatic non-squamous non-small cell lung cancer, according to the results from the SKYSCRAPER-06 study presented at the ESMO Immuno-Oncology Congress 2024 (LBA2).
Pembrolizumab plus chemotherapy is the standard of care for the first-line treatment of patients whose tumours do not harbour EGFR or ALK alterations, irrespective of PD-L1 expression. TIGIT (T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains) plays an important role in regulating immune responses at the immune synapses of T and NK cells, and is a novel promising target in immuno-oncology.
SKYSCRAPER-06 is a global, phase II/III, randomised, double-blind, placebo-controlled trial involving 542 patients who had not received prior treatment. Baseline characteristics were similar across arms, however there were more men (68% vs 62%), fewer patients with PD-L1 tumour proportion score (TPS) <1% (34% vs 42%) and more patients with baseline liver metastases (14% vs 9%) in the tiragolumab plus atezolizumab and chemotherapy arm. Treatments (tiragolumab 600 mg plus atezolizumab 1200 mg plus carboplatin/cisplatin plus pemetrexed or placebo plus pembrolizumab pembro 200 mg plus carboplatin/cisplatin plus pemetrexed) were given every three weeks for four cycles, and followed by maintenance therapy until disease progression, loss of clinical benefit, unacceptable toxicity or consent withdrawal.
At data cutoff, the combination of tiragolumab plus atezolizumab and chemotherapy showed reduced efficacy compared to the standard therapy, with a median PFS of 8.3 versus 9.9 months (hazard ratio [HR] 1.27; 95% confidence interval [CI] 1.02,1.57; p=0.99) and an OS of 18.9 versus 23.1 months (HR 1.33; 95% CI: 1.02, 1.73; p=0.98) (Figure). Results were observed across all clinically meaningful subgroups, including PD-L1.
Safety was similar in the two arms and no new or unexpected safety signals were identified.
Based on the disappointing findings, the SKYSCRAPER-06 study is being terminated.
“There are many phase II studies that are evaluating different antibody anti-TIGIT, such as domvanalimab in the ARC-7 as a single agent or in combination therapy (NCT04262856), belrestotug plus dostarlimab in the GALAXIES-Lung 201 (Annals of Oncology, Volume 35, S1242 - S1243) and tiragolumab plus atezolizumab in the CITYSCAPE (Lancet Oncol. 2022 Jun;23(6):781-792), which provided encouraging results. However, there are two phase III trials that are negative, i.e. the SKYSCRAPER-01 which has been recently press released, and now the SKYSCRAPER-06”, said Prof. Marcello Tiseo, University of Parma, Parma, Italy, who was the invited discussant to comment on the findings in Geneva. “For the SKYSCRAPER-06, the potential explanation is an unbalance between the two arms, with more patients with liver metastasis in the experimental arm, a numerically higher rate of grade 5 AEs in the experimental arm, and the preclinical data hypothesis that concurrent chemotherapy may attenuate the activity of tiragolumab plus atezolizumab. But this explanation is not valid for the negative results of the SKYSCRAPER-01.” Tiseo also concluded that, taken together, these negative findings raise some doubts about the real relevance of TIGIT as a target.
