Tiragolumab Plus Atezolizumab/Chemo Misses PFS End Point in Extensive-Stage SCLC

The addition of the anti-TIGIT immunotherapy tiragolumab to atezolizumab (Tecentriq) plus carboplatin/etoposide failed to significantly improve progression-free survival (PFS) over atezolizumab/chemotherapy alone when used in the frontline treatment of patients with extensive-stage small cell lung cancer (ES-SCLC), missing the co-primary end point of the phase 3 SKYSCRAPER-02 trial (NCT04256421).¹

The co-primary end point of overall survival (OS) was also not met at the time of the interim analysis and is unlikely to reach statistical significance at the planned final analysis. However, the combination was found to have acceptable tolerability, with no new safety signals observed.

More detailed data from the trial will be shared at an upcoming medical conference, according to Roche.

“Today’s outcome is disappointing as we had hoped to continue building on the advances of [atezolizumab] in ES-SCLC, which remains difficult to treat,” Levi Garraway, MD, PhD, chief medical officer and head of global product development at Roche, stated in a press release.

An immune checkpoint inhibitor with an intact Fc region, tiragolumab was designed to selectively bind to TIGIT, which is known to suppress the response of the immune system to cancer. Preclinical data have indicated that the agent can serve as an immune amplifier when paired with other immunotherapeutic agents.

Although the TIGIT pathway is distinct to the PD-L1/PD-1 pathway, it is also complementary. Investigators have hypothesized that the combination of tiragolumab and an immunotherapy like atezolizumab could serve to overcome immune suppression and essentially restore response.

The global, placebo-controlled, double-blinded SKYSCRAPER-02 trial enrolled patients with histologically or cytologically confirmed ES-SCLC who have not previously received systemic treatment.² To be eligible for enrollment, patients needed to have an ECOG performance status of 0 or 1, measurable disease per RECIST v1.1 criteria, acceptable hematologic and end-organ function, and they needed to be treatment free for at least 6 months since their last chemoradiation.

If patients had symptomatic or actively progressing central nervous system metastases, malignancies other than SCLC within 5 years before randomization, active or a history of autoimmune disease or immune deficiency, or human immunodeficiency virus, active hepatitis B or C virus, or severe infection at the time of randomization, they were excluded.

A total of 490 patients were enrolled to the trial, and they were randomized 1:1 to receive intravenous (IV) tiragolumab at 600 mg on day 1 of each 21-day cycle plus atezolizumab and carboplatin/etoposide or placebo plus atezolizumab and carboplatin/etoposide. All patients received IV atezolizumab at 1200 mg on day 1 of each 21-day cycle, IV carboplatin on day 1 of each 21-day cycle for 4 cycles followed by etoposide at 100 mg/m2 on days 1, 2, and 3 of each 21-day cycle for 4 cycles.

The co-primary end points of the trial were OS and PFS in the primary analysis set, which was comprised of all randomized patients whose cancer had not spread to the brain. Important secondary end points included OS and PFS in all randomized patients and safety.

Previously, tiragolumab was granted a breakthrough therapy designation from the FDA for use in combination with atezolizumab in the first-line treatment of patients with metastatic NSCLC whose tumors are PD-L1 high and do not harbor any EGFR or ALK aberrations.³

The phase 2 CITYSCAPE trial (NCT03563716) enrolled treatment-naïve patients with stage IV non–small cell lung cancer (NSCLC) who had EGFR or ALK wild-type disease. To participate, patients needed to have a PD-L1 tumor proportion score (TPS) of 1% or higher per 22C3 immunohistochemistry and local or central assay.⁴

A total of 135 patients were randomized 1:1 to receive IV tiragolumab at 600 mg every 3 weeks in combination with IV atezolizumab at 1200 mg every 3 weeks (n = 67), or IV placebo at 600 mg every 3 weeks plus IV atezolizumab at 1200 mg every 3 weeks (n = 68). Treatment was administered until progressive disease or clinical benefit was lost. Key stratification factors included PD-L1 TPS (1% to 49% vs more than 50%), histology (nonsquamous vs squamous), and tobacco use (yes vs no).

The co-primary end points of this research were objective response rate (ORR) and PFS. Secondary end points included duration of response, OS, and safety.

At a median follow-up of 30.4 months, the combination produced a median PFS of 5.6 months (95% CI, 4.2-10.4) per investigator assessment vs 3.9 months (95% CI, 2.7-4.5) with atezolizumab alone in the intention-to-treat (ITT) population. The median OS in the investigative and control arms was 23.2 months (95% CI, 14.1-31.5) and 14.5 months (95% CI, 9.6-20.4), respectively.

At the time of the primary analysis, which had a data cutoff date of June 30, 2019, and a median follow-up of 5.9 months, the tiragolumab combination produced a clinically meaningful improvement in ORR and PFS in the ITT population vs atezolizumab monotherapy. That benefit was maintained with the additional follow-up, with a greater magnitude of improvement noted in the patient subset who had a PD-L1 TPS of 50% or less.

The phase 3 SKYSCRAPER-01 trial (NCT04294810) is currently ongoing to confirm the results yielded in CITYSCAPE. Here, the safety and efficacy of tiragolumab plus atezolizumab is being compared with atezolizumab alone in patients with previously untreated locally advanced, unresectable or metastatic PD-L1–selected NSCLC without an EGFR mutation or an ALK translocation.⁵

“We look forward to seeing additional data from the upcoming phase 3 trial in PD-L1–high NSCLC based on encouraging results from the CITYSCAPE study,” Garraway added.

References

1. 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 March 30, 2022. https://bit.ly/36HFr7N
2. A study of atezolizumab plus carboplatin and etoposide with or without tiragolumab in patients with untreated extensive-stage small cell lung cancer (SKYSCRAPER-02). ClinicalTrials.gov. Updated March 17, 2022. Accessed March 30, 2022. https://clinicaltrials.gov/ct2/show/NCT04256421
3. 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 March 30, 2022. http://bit.ly/2LoNrj2
4. Cho BC, Rodriguez-Abreu S, Hussein M, et al. LBA2 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 7):S1428. doi:10.1016/j.annonc.2021.10.217
5. 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 March 30, 2022. https://clinicaltrials.gov/ct2/show/NCT04294810