EMA Accepts Marketing Authorization Applications for Tislelizumab in Select ESCC and NSCLC

Mark Lanasa, MD, PhD

Marketing authorization applications (MAAs) seeking the approval of tislelizumab (BGB-A317) in patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) following previous systemic chemotherapy and in select patients with non–small cell lung cancer have been submitted to the European Medicines Agency (EMA).¹

Specifically, the NSCLC application is seeking the approval of tislelizumab as a single agent in adult patients with locally advanced or metastatic NSCLC following previous chemotherapy, for use in combination with carboplatin and paclitaxel or nab-paclitaxel (Abraxane) for the frontline treatment of those with locally advanced or metastatic squamous NSCLC, and for use in combination with pemetrexed and platinum-containing chemotherapy in the frontline treatment of patients with locally advanced or metastatic nonsquamous NSCLC whose tumors do not harbor EGFR or ALK mutations.

The MAA for the agent in ESCC is supported by data from the phase 3 RATIONALE 302 trial (NCT03430843), and the MAA for tislelizumab in NSCLC is based on data from 3 phase 3 trials (NCT03358875, NCT03594747, and NCT03663205).

“In our global phase 3 trials in second-line ESCC and NSCLC, tislelizumab monotherapy demonstrated significant improvements in overall survival [OS] and was generally well tolerated in these patient groups,” Mark Lanasa, MD, PhD, senior vice president and chief medical officer of solid tumors at BeiGene, Ltd., stated in a press release. “…These first submissions for tislelizumab to the EMA highlight the momentum in our collaboration with Novartis, and we look forward to continued progress as they submit tislelizumab for approvals in their licensed territories.”

Tislelizumab in ESCC: Insights from RATIONALE 302

In the RATIONALE 302 trial, investigators compared the safety and efficacy of tislelizumab vs chemotherapy in the second-line treatment of patients with advanced or metastatic ESCC. To participate, patients must have progressed during or following frontline systemic treatment, and they needed to have an ECOG performance status of 0 or 1.²

A total of 512 patients were enrolled to the trial, and they were randomized 1:1 to receive tislelizumab intravenously (IV) at a dose of 200 mg every 3 weeks or investigator-selected chemotherapy, which could have included IV paclitaxel at a dose ranging from 135 mg/m² to 175 mg/m² every 3 weeks or 80 mg/m² to 100 mg/m² weekly, IV docetaxel at 75 mg/m² every 3 weeks, or IV irinotecan at 125 mg/m² on days 1 and 8 every 3 weeks.

Key stratification factors included region (Asia except for Japan vs Japan vs Europe/North America), performance status (0 vs 1), and chemotherapy option (paclitaxel vs docetaxel vs irinotecan).

The primary end point of the trial was OS in all randomized patients, and a key secondary end point was OS in all patients with a PD-L1 combined positive score (CPS) of 10% or higher. Other secondary end points included progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and safety.

At the time of the 2021 ASCO Annual Meeting, a total of 512 patients underwent randomization; 256 comprised the tislelizumab arm and 256 comprised the chemotherapy arm. However, 255 patients and 240 patients in the investigative and control arms, respectively, received treatment on study.

The data cutoff date for the final analysis was December 1, 2020. The median follow-up for tislelizumab was 8.5 months (range, 0.2-31.7) and it was 5.8 months (range, 0-30.8) for chemotherapy.

The median age across the arms was 62.5 years, and most patients were male, from Asia, had an ECOG performance status of 1, and had metastatic disease at baseline. Moreover, 34.8% of those in the tislelizumab arm had a PD-L1 CPS of 10% or higher vs 26.6% of those in the chemotherapy arm. Prior therapies received in the investigative and control arms, respectively, included surgery (36.7% vs 38.7%), radiotherapy (66.0% vs 63.7%), and platinum-based chemotherapy (97.3% vs 98.4%).

Tislelizumab was found to significantly improve OS vs chemotherapy in all randomized patients, as well as in the subset of patients who had a PD-L1 CPS of 10% or higher. In the all-randomized population, the median OS was 8.6 months (95% CI, 7.5-10.4) with tislelizumab vs 6.3 months (95% CI, 5.3-7.0) with chemotherapy (HR, 0.70; 95% CI, 0.57-0.85; P = .0001), which translated to a 30% reduction in the risk of death. The 6-month OS rates in the investigative and control arms were 62.3% and 51.8%, respectively; at 12 months, these rates were 37.4% and 23.7%, respectively.

In the subset of patients with a PD-L1 CPS of 10% or higher, the median OS with tislelizumab (n = 89) was 10.3 months (95% CI, 8.5-16.1) vs 6.8 months (95% CI, 4.1-8.3) with chemotherapy (n = 68), which translated to a 46% reduction in the risk of death (HR, 0.54; 95% CI, 0.36-0.79; P = .0006). The 6-month OS rates with tislelizumab and chemotherapy in this subset were 67.4% and 50.8%, respectively; the 12-month OS rates were 44.0% and 27.0%, respectively.

Notably, the survival benefit achieved with tislelizumab was noted across all predefined subgroups, including PD-L1 expression status, race, and region.

The median PFS with tislelizumab in all randomized patients was 1.6 months (95% CI, 1.4-2.7) vs 2.1 months (95% CI, 1.5-2.7) with chemotherapy (HR, 0.83; 95% CI, 0.67-1.01), with the PFS Kaplan-Meier curves beginning to separate at approximately 3 months after randomization; the curves were found to favor tislelizumab. The 6-month PFS rate with tislelizumab was 21.7% vs 14.9% with chemotherapy; at 12 months, these rates were 12.7% vs 1.9%, respectively.

Tislelizumab elicited an ORR of 20.3% (95% CI, 15.6%-25.8%) vs 9.8% (95% CI, 6.4%-14.1%) with chemotherapy (odds ratio, 2.4; 95% CI, 1.4-4.0). The best overall response in the investigative arm was a complete response for 2.0% of patients, a partial response for 18.4% of patients, stable disease for 26.6% of patients, and disease progression for 45.3% of patients.

The median DORs in the tislelizumab and chemotherapy arms were 7.1 months (95% CI, 4.1-11.3) and 4.0 months (95% CI, 2.1-8.2), respectively. Moreover, 19.2% of those who received tislelizumab had an ongoing response at data cutoff vs 0% of those who were given chemotherapy.

Tislelizumab was found to have a favorable toxicity profile vs chemotherapy, and no new safety signals were observed. The most common treatment-related adverse effects with tislelizumab included increased aspartate aminotransferase (AST; 11.4%), anemia (11.0%), hypothyroidism (10.2%), fatigue (7.5%), decreased appetite (6.3%), diarrhea (5.5%), asthenia (4.7%), malaise (3.9%), weight decreased (3.1%), nausea (2.7%), leukopenia (2.7%), white blood cell count decreased (2.0%), vomiting (1.6%), constipation (1.6%), neutrophil count decreased (1.2%), and neutropenia (0.8%).

The MAA submission also included safety findings from a total of 1972 patients who received tislelizumab as a single agent across 7 clinical trials.

In September 2021, the FDA accepted for review a biologics license application seeking the approval of tislelizumab in patients with unresectable or locally advanced or metastatic ESCC following prior systemic therapy based on findings from RATIONALE 302.³

Tislelizumab in NSCLC: RATIONALE 303 Highlights

The open-label, multicenter, global, phase 3 RATIONALE 303 trial was launched to examine the safety and efficacy of tislelizumab vs docetaxel in the second- or third-line treatment of patients with locally advanced or metastatic NSCLC who progressed on previous platinum-based chemotherapy.⁴

The trial enrolled those who were 18 years of age or older who had an ECOG performance status of 0 or 1, acceptable hematologic and end-organ function, and a life expectancy of over 12 weeks.5 Patients could not have previously received docetaxel or a PD-1, PD-L1, or CTLA-4 inhibitor. Other exclusion criteria included tumors harboring EGFR or ALK aberrations, those with a history of severe hypersensitivity reactions to other monoclonal antibodies, or a history of interstitial lung disease.

A total of 805 patients were randomized 2:1 to IV tislelizumab at 200 mg every 3 weeks or IV docetaxel at 75 mg/m² every 3 weeks.

The dual primary end points of the trial were OS in the intent-to-treat (ITT) population and in the subset of patients determined to have a high PD-L1 expression. Important secondary end points included ORR, DOR, PFS, and safety.

Data from a prespecified OS interim analysis in the ITT population showed that the median OS with tislelizumab was 17.2 months (95% CI, 15.28-20.04) vs 11.9 months (95% CI, 10.18-13.93) with docetaxel, translating to a 36% reduction in the risk of death and meeting the primary end point of the trial (HR, 0.64; 95% CI, 0.527-0.778; P < .0001).

In the subset of patients with high PD-L1 expression, the median OS in the investigative and control arms was 19.1 months (95% CI, 16.82-25.79) vs 11.9 months (95% CI, 8.90-14.03), respectively (HR, 0.52; 95% CI, 0.384-0.713; P < .0001).

Additionally, the median PFS with tislelizumab was 4.1 months (95% CI, 3.75-5.03) vs 2.6 months (95% CI, 2.17-3.78) with docetaxel (HR, 0.64; 95% CI, 0.533-0.758; P < .0001). The 12-month PFS rates in the investigative and control arms were 23.3% and 5.7%, respectively.

Tislelizumab produced an ORR of 21.9% vs just 7.0% with docetaxel, which translated to a difference of 14.9% between the arms (95% CI, 10.26%-19.56%; P < .0001). The median DOR with tislelizumab was 13.5 months (95% CI, 8.54-21.78) vs 6.2 months (95% CI, 2.10-7.16) with docetaxel.

Regarding safety, 95.3% of the 509 patients who received tislelizumab experienced at least 1 treatment-emergent toxicity. The most common treatment-emergent adverse effects (TEAEs) included anemia (28.5%), increased alanine aminotransferase (ALT; 19.9%), and cough (19.5%). Of the 254 patients given docetaxel, 98.4% experienced TEAEs, with the most common being alopecia (47.3%), anemia (43.4%), and decreased neutrophil count (36.8%).

Grade 3 or higher TEAEs were reported in 38.6% of those on the investigative arm and 74.8% of those on the control arm; serious TEAEs were experienced by 32.6% and 32.2% of patients, respectively. The most common immune-mediated TEAE of any grade in the tislelizumab arm was hypothyroidism (7.5%), and the most common grade 3 or higher immune-mediated TEAE with this agent was pneumonitis (2.2%).

Moreover, 10.5% of those on the tislelizumab arm discontinued treatment because of TEAEs vs 12.4% of those on the docetaxel arm. A total of 32 patients on the investigative arm and 11 patients on the control arm experienced a TEAE that proved to be fatal.

Tislelizumab in Frontline NSCLC: Insights From RATIONALE 307

“In the 2 phase 3 studies in first-line NSCLC, tislelizumab in combination with chemotherapy demonstrated significant improvements in PFS compared with chemotherapy alone in both nonsquamous and squamous histology, and the addition of tislelizumab to chemotherapy was generally well tolerated with no new safety signals observed,” Lanasa added in the release.

The multicenter, open-label RATIONALE 307 trial enrolled adults in China who had treatment-naïve, histologically confirmed, locally advanced or metastatic squamous NSCLC that was not amenable to surgery or not suitable for chemoradiation.⁶ To participate, patients needed to have an ECOG performance status of 0 or 1, and at least 1 measurable lesion.

Those randomized to arm A of the trial were given tislelizumab at 200 mg plus paclitaxel at 175 mg/m² and carboplatin area under the curve (AUC) 5 on day 1 once every 3 weeks. Those in arm B received tislelizumab at 200 mg and carboplatin AUC 5 on day 1 once every 3 weeks in combination with nab-paclitaxel (Abraxane) at 100 mg/m² on days 1, 8, and 15, every 3 weeks. Those in arm C received paclitaxel at 175 mg/m2 plus carboplatin on day 1 once every 3 weeks.

In arms A and B, the triplet regimens were given for 4 to 6 treatment cycles, and this was followed by maintenance treatment with tislelizumab until progressive disease, unacceptable toxicity, or treatment discontinuation. Crossover from arm C to tislelizumab maintenance was permitted upon progression.

Patients were stratified based on disease stage (IIIB vs IV) and PD-L1 expression (<1% vs 1% to 49% vs ≥50%). The primary end point of the trial was PFS.

At a data cutoff of December 6, 2019, the median follow-up for those with stage IIIB disease in arms A, B, and C were 9.3 months, 8.8 months, and 9.1 months, respectively; for those with stage IV disease, the median follow-up in each of these arms was 8.3 months, 8.6 months, and 7.7 months, respectively.

Data showed that tislelizumab resulted in a numerically longer PFS in arms A and B vs C for both populations. For those with stage IIIB disease, the median PFS for arm A (n = 38) was 9.8 months (95% CI, 6.0–not estimable [NE]) vs 5.6 months (95% CI, 4.2-7.4) in arm C (n = 44; HR, 0.402; 95% CI, 0.215-0.750). The median PFS was 11.0 months (95% CI, 7.6-NE) in arm B (n = 40; HR, 0.372; 95% CI, 0.202-0.686).

The ORR in arms A, B, and C were 84.2% (95% CI, 68.7%-94.0%), 82.5% (95% CI, 67.2%-92.7%), and 59.1% (95% CI, 43.2%-73.7%), respectively. The ORR difference in arms A and B vs arm C was 25.3% (95% CI, 6.43%-44.18%) and 23.4% (95% CI, 4.23%-42.55%), respectively. The median DOR was NE (95% CI, 5.03-NE) in arm A, compared with 4.0 months (95% CI, 2.66-5.59) in arm C (HR, 0.274; 95% CI, 0.127-0.590). The median DOR in arm B was 9.7 months (95% CI, 4.67-NE) vs arm C (HR, 0.344; 95% CI, 0.162-0.729).

Among those with stage IV disease, the median PFS for arm A (n = 82) was 7.6 months (95% CI, 5.6-7.8) vs 5.2 months (95% CI, 4.2-5.6) for arm C (n = 77; HR, 0.570; 95% CI, 0.376-0.862). The median PFS was 7.4 months (95% CI, 5.6-9.9) for arm B (n = 79; HR, 0.537; 95% CI, 0.350-0.824).

The ORRs in arm A, B, and C were 67.1% (95% CI, 55.8%-77.1%), 70.9% (95% CI, 59.6%-80.6%), and 44.2% (95% CI, 32.8%-55.9%), respectively. The ORR difference in arms A and B vs arm C were 23.0% (95% CI, 7.99%-37.92%) and 26.4% (95% CI, 11.62%-41.26%), respectively. The median DOR in arm A was 6.9 months (95% CI, 3.65-NE) vs 4.2 months (95% CI, 2.83-5.72) in arm C (HR, 0.622; 95% CI, 0.343-1.126). The median DOR in arm B was 8.6 months (95% CI, 4.80-NE) vs arm C (HR, 0.530; 95% CI, 0.290-0.969).

The most common TRAEs reported included anemia, decreased neutrophil count, alopecia, decreased white blood cell count, leukopenia, neutropenia, thrombocytopenia, increased ALT, decreased appetite, and increased AST.

References

1. BeiGene announces European Medicines Agency acceptance of marketing authorization applications for tislelizumab for the treatment of patients with ESCC and NSCLC. News release. BeiGene, Ltd.; April 6, 2022. Accessed April 6, 2022. https://bwnews.pr/3NRpuwE
2. Shen L, Kato K, Kim, S-B, et al. RATIONALE 302: randomized, phase 3 study of tislelizumab versus chemotherapy as second-line treatment for advanced unresectable/metastatic esophageal squamous cell carcinoma. J Clin Oncol. 2021;39(suppl 15):4012. doi:10.1200/JCO.2021.39.15_suppl.4012
3. BeiGene announces US FDA acceptance of biologics license application for tislelizumab in esophageal squamous cell carcinoma. News release. BeiGene, Ltd.; September 13, 2021. Accessed April 6, 2022. https://bit.ly/2YJw17s
4. BeiGene presents interim analysis results of RATIONALE 303 trial of tislelizumab in second- or third-line non-small cell lung cancer at the AACR Annual Meeting 2021. News release. BeiGene, Ltd.; April 12, 2021. Accessed April 6, 2022. https://bit.ly/3NRpTza
5. Comparison of efficacy and safety of anti-PD-1 antibody BGB-A317 versus docetaxel as treatment in second- or third-line setting in participants with NSCLC. ClinicalTrials.gov. Updated August 12, 2020. Accessed April 6, 2022. https://clinicaltrials.gov/ct2/show/NCT03358875
6. Lu, S, Yu X, Wang J, et al. RATIONALE 307: a subgroup analysis of tislelizumab plus chemotherapy vs chemotherapy alone as first-line treatment for stage IIIB advance squamous NSCLC. Presented at: 2021 World Conference on Lung Cancer; September 8-14, 2021. Abstract P17.02