Tislelizumab Receives EU Approval in 3 Indications for First- and Second-Line NSCLC

The European Commission (EC) has approved tislelizumab (Tizveni) across 3 indications for the first- and second-line treatment of adult patients with non–small cell lung cancer (NSCLC).¹

The 3 NSCLC indications for tislelizumab include the following:

• In combination with carboplatin and paclitaxel or nab-paclitaxel (Abraxane) for the first-line treatment of adult patients with squamous NSCLC who have locally advanced disease and are not candidates for surgical resection or platinum-based chemoradiation; or who have metastatic disease.
• In combination with pemetrexed and platinum-containing chemotherapy for the first-line treatment of adult patients with nonsquamous NSCLC whose tumors have PD-L1 expression on at least 50% of tumor cells with no EGFR or ALK mutations. Patients need to have locally advanced NSCLC and be ineligible for surgical resection or platinum-based chemoradiation, or metastatic NSCLC.
• As monotherapy for the treatment of adult patients with locally advanced or metastatic NSCLC following platinum-based therapy. Patients with EGFR-mutant or ALK-positive NSCLC should have also received targeted therapies prior to treatment with tislelizumab.

Clinical data from the phase 3 RATIONALE-307 (NCT03594747), RATIONALE-304 (NCT03663205), and RATIONALE-303 (NCT03358875) trials, respectively, supported these regulatory decisions. Prior to the approvals, all 3 indications received a positive recommendation from the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use in February 2024.²

“Tislelizumab is foundational for BeiGene’s solid tumor portfolio and has demonstrated its potential across multiple tumor types, including NSCLC, in which there remains a significant unmet need at all stages of the disease,” Mark Lanasa, MD, PhD, the chief medical officer of Solid Tumors at BeiGene, stated in a press release.¹ “Today’s EC authorization marks the second in the region for tislelizumab, with both NSCLC and locally advanced or metastatic esophageal squamous cell carcinoma [ESCC] now approved in the European Union. Second-line use in ESCC was also approved just weeks ago by the FDA, putting us well on our way to fulfilling our commitment to bring this innovative therapy to many more patients around the world.”

Notably, tislelizumab was approved in these 3 indications under the brand name Tizveni. BeiGene announced that in the second half of 2024, the company plans to combine the NSCLC indications with the second-line ESCC indication, which carries the brand name Tevimbra (tislelizumab-jsgr).

RATIONALE-307

The open-label, randomized RATIONALE-307 trial evaluated first-line tislelizumab plus chemotherapy in 360 patients with untreated, advanced squamous NSCLC.^1,3 Patients were required to have an ECOG performance status of 0 or 1; 1 or more measurable lesions; a life expectancy greater than 12 weeks; and adequate organ function. Those with EGFR sensitizing mutations or ALK fusions; prior exposure to systemic anticancer therapy or therapies targeting PD-(L)1; and a history of interstitial lung disease (ILD) or noninfectious pneumonitis were ineligible to enroll.

Findings published in JAMA Oncology demonstrated that tislelizumab plus chemotherapy significantly improved progression-free survival (PFS) vs standard-of-care chemotherapy, meeting the primary end point of the trial. Moreover, the combination produced a superior objective response rate (ORR) vs chemotherapy. At a median follow-up of 8.6 months (95% CI, 8.1-9.0), the median independent review committee (IRC)–assessed PFS was 7.6 months with tislelizumab and paclitaxel/carboplatin vs 5.5 months for chemotherapy alone (HR, 0.524; 95% CI, 0.370-0.742; P < .001). Additionally, the median PFS was 7.6 months for the tislelizumab and nab-paclitaxel/carboplatin combination (HR vs chemotherapy alone, 0.478; 95% CI, 0.336-0.679; P < .001).³

Tislelizumab plus chemotherapy had a manageable safety and tolerability profile regardless of PD-L1 expression. The most frequently observed grade 3 or higher treatment-emergent adverse effects (TEAEs) were decreased neutrophil levels, neutropenia, and leukopenia.¹

RATIONALE-304

In the open-label, randomized, multicenter RATIONALE-304 trial, 334 adult patients with histologically confirmed locally advanced or metastatic nonsquamous NSCLC were treated with tislelizumab plus carboplatin or cisplatin and pemetrexed vs chemotherapy alone.^1,4 Patients were required to have an ECOG performance status of 1 or less; have 1 or more measurable lesions per RECIST v1.1 criteria; have no previous exposure to systemic chemotherapy for advanced or metastatic nonsquamous NSCLC; and be ineligible for curative surgery or radiotherapy. Patients with EGFR-sensitizing mutations or ALK translocations were not eligible.

According to data published in the Journal of Thoracic Oncology, first-line tislelizumab and chemotherapy produced a statistically significant PFS benefit vs chemotherapy alone (HR, 0.645; 95% CI, 0.462-0.902; P = .0044), and improved ORR and duration of response.⁴ At a median follow-up of 9.8 months (95% CI, 9.23–10.38), the median IRC-assessed PFS in the overall population was 9.7 months (95% CI, 7.7-11.5) for the tislelizumab combination groups vs 7.6 months(95% CI, 5.6-8.0) with platinum and pemetrexed alone. The most common grade 3 or higher TEAEs were neutropenia and leukopenia, and these were primarily associated with chemotherapy.¹

RATIONALE-303

The open-label, randomized RATIONALE 303 study evaluated second- or third-line tislelizumab plus docetaxel in 805 patients with histologically confirmed, locally advanced or metastatic squamous or nonsquamous NSCLC.^1,5 Eligibility criteria included disease progression on at least 1 prior platinum-based regimen and an ECOG performance score of 0 or 1. Notably, those with treated, stable brain metastases were also allowed onto the study. Prior exposure to docetaxel for metastatic disease or previous checkpoint inhibitors targeting PD-1, PD-L1, or CTLA-4, as well as known EGFR mutations or ALK gene translocations, excluded patients from enrollment.

Data from the Journal of Thoracic Oncology showed that tislelizumab generated a statistically significant and clinically meaningful overall survival (OS) benefit in the intent-to-treat population vs docetaxel alone, regardless of PD-L1 expression (HR, 0.66; 95% CI, 0.56-0.79; P < .0001).⁵ At the final analysis data cutoff in June 2021, the median OS was 16.9 months (95% CI, 15.2-19.1) vs 11.9 months (95% CI, 9.6-13.5) with tislelizumab vs docetaxel, respectively. The most frequently observed grade 3 or higher TEAEs were pneumonia, anemia, and dyspnea.¹

Future Directions for Tislelizumab

In September 2023, the EC approved tislelizumab monotherapy for adult patients with unresectable, locally advanced or metastatic ESCC after prior platinum-based chemotherapy.6

Single-agent tislelizumab was also approved by the FDA in March 2024 for adult patients with unresectable or metastatic ESCC after previous systemic chemotherapy who had not received a PD-1/PD-L1 inhibitor.⁷

The agent is currently under review by the EMA and the FDA for the first-line treatment of patients with unresectable, recurrent, locally advanced or metastatic ESCC, as well as for the first-line treatment of those with gastric or gastroesophageal junction cancers.

Additionally, neoadjuvant tislelizumab plus platinum-based doublet chemotherapy followed by surgery and adjuvant tislelizumab is currently under evaluation in the phase 3 RATIONALE-315 trial (NCT04379635).⁸ Findings showed a significant improvement in event-free survival with the regimen vs neoadjuvant placebo plus platinum-based doublet chemotherapy followed by surgery and adjuvant placebo in resectable NSCLC.

“NSCLC remains one of the most common and deadly cancers in Europe, with 50% of patients diagnosed already progressed to advanced stages, making it difficult to treat,” Luis Paz-Ares, MD, PhD, who serves as Head of the Medical Oncology Service at the Hospital Universitario 12 de Octubre, in Madrid, added in a press release.¹ “Across 3 phase 3 studies, tislelizumab has been shown to improve outcomes for patients with certain types of NSCLC, providing a new option for those facing the disease.”

References

1. BeiGene receives European Commission approval for tislelizumab as treatment for non-small cell lung cancer. News release. BeiGene. April 23, 2024. Accessed April 23, 2024. https://ir.beigene.com/news/beigene-receives-european-commission-approval-for-tislelizumab-as-treatment-for-non-small-cell-lung-cancer/674be3d8-3577-48c9-be74-b57e5c1aad93/
2. BeiGene receives positive CHMP opinion for tislelizumab as treatment for non-small cell lung cancer. News release. BeiGene. February 26, 2024. Accessed April 23, 2024. https://ir.beigene.com/news/beigene-receives-positive-chmp-opinion-for-tislelizumab-as-treatment-for-non-small-cell-lung-cancer/76c25106-81ac-4654-b382-4ba84e6038f3/
3. Wang J, Lu S, Yu X, et al. Tislelizumab plus chemotherapy vs chemotherapy alone as first-line treatment for advanced squamous non–small-cell lung cancer. JAMA Oncol. 2021;7(5):709-717. doi:10.1001/jamaoncol.2021.0366
4. Lu S, Wang J, Yu Y, et al. Tislelizumab plus chemotherapy as first-line treatment for locally advanced or metastatic nonsquamous NSCLC (RATIONALE 304): A randomized phase 3 trial. J Thorac Oncol. 2021 Sep;16(9):1512-1522. doi:10.1016/j.jtho.2021.05.005.
5. Zhou C, Huang D, Fan Y, et al. Tislelizumab versus docetaxel in patients with previously treated advanced NSCLC (RATIONALE-303): A phase 3, open-label, randomized controlled trial. J Thorac Oncol. 2023 Jan;18(1):93-105. doi:10.1016/j.jtho.2022.09.217.
6. BeiGene announces positive regulatory updates in Europe and the U.S. after recently regaining global rights for Tevimbra. News release. BeiGene. September 19, 2023. Accessed April 23, 2024. https://ir.beigene.com/news/beigene-announces-positive-regulatory-updates-in-europe-and-the-u-s-after-recently-regaining-global-rights/5e4692d6-d726-4989-a659-49dc97d4d7ed/
7. BeiGene receives FDA approval for Tevimbra for the treatment of advanced or metastatic esophageal squamous cell carcinoma after prior chemotherapy. News release. BeiGene. March 14, 2024. Accessed April 23, 2024. https://ir.beigene.com/news/beigene-receives-fda-approval-for-tevimbra-for-the-treatment-of-advanced-or-metastatic-esophageal-squamous/20eb032c-15ce-456a-a852-39c88a28d811/
8. Yue D, Wang W, Liu H, et al. RATIONALE-315: event-free survival (EFS) and overall survival (OS) of neoadjuvant tislelizumab (TIS) plus chemotherapy (CT) with adjuvant TIS in resectable non-small cell lung cancer (NSCLC). Ann Oncol. 2024;35(3):P332-333. doi:10.1016/j.annonc.2024.01.005