Tislelizumab Application Accepted in China for Frontline Advanced NSCLC

The China National Medical Products Administration has accepted a supplemental new drug application (sNDA) for tislelizumab in combination with chemotherapy for the frontline treatment of patients with advanced nonsquamous non–small cell lung cancer (NSCLC).¹

“We are pleased to submit our second sNDA in first-line advanced NSCLC and the fourth potential indication for tislelizumab in China,” Xiaobin Wu, PhD, general manager of China and president of BeiGene, the developer of tislelizumab, said in a press release. “We credit the continued momentum of our tislelizumab clinical program to the strong expertise of our teams and the support of clinicians and patients who participated the trials. We have 3 additional phase 3 trials for tislelizumab in lung cancer and we are looking forward to continuing to expand the label for [the agent].”

The submission of the sNDA in nonsquamous NSCLC was reinforced by clinical data from the phase 3 BGB-A317-304 trial (NCT03663205), in which the PD-1 inhibitor combined with pemetrexed and platinum chemotherapy resulted in a significant improvement in progression-free survival (PFS) compared with chemotherapy alone in the first-line treatment setting for patients with nonsquamous disease, according to data presented during the 2020 ASCO Virtual Scientific Program.²

The open-label multicenter phase 3 trial enrolled 334 patients with treatment-naïve stage IIIB or stage IV nonsquamous disease whose tumors did not harbor EGFR mutations or ALK aberrations. In the trial, patients were randomized in a 2:1 ratio to receive either tislelizumab at 200 mg every 3 weeks plus pemetrexed and investigator’s choice of either cisplatin or carboplatin, or pemetrexed and platinum chemotherapy alone. The primary end point of the trial was PFS per an independent review committee. Secondary end points included overall survival (OS) and safety.

Previously, in January 2020, data from the planned interim analysis of the phase 3 BGB-A317-307 trial were reported. Results showed that frontline tislelizumab in combination with chemotherapy also improved PFS in patients with advanced squamous disease, meeting the primary end point of the trial.³ Specifically, the analysis demonstrated that tislelizumab combined with either carboplatin/paclitaxel or with carboplatin/nab-paclitaxel (Abraxane) crossed the prespecified efficacy boundary compared with carboplatin plus paclitaxel alone.

In this multicenter, randomized, phase 3 trial, the safety and efficacy of the PD-1 inhibitor in combination with either carboplatin/paclitaxel or carboplatin/nab-paclitaxel was compared with carboplatin plus paclitaxel alone in a total of 360 treatment-naïve Chinese patients with stage IIIB/IV squamous disease, regardless of PD-L1 expression.

In the trial, patients were randomized 1:1:1 to arm A comprised of tislelizumab at 200 mg every 3 weeks plus paclitaxel/carboplatin, arm B comprised of tislelizumab same dosing schedule plus nab-paclitaxel and carboplatin, and arm C comprised of paclitaxel and carboplatin. Paclitaxel, nab-paclitaxel, and carboplatin were given for 4 to 6 treatment cycles, while the PD-1 inhibitor was administered until progressive disease, unacceptable toxicity, or discontinuation. Notably, crossover was permitted at the time of disease progression for those enrolled on the control arm. The primary end point of the trial was PFS, and key secondary end points included objective response rate (ORR), duration of response, OS, and safety.

Results presented during the 2020 ASCO Virtual Scientific Program showed that in patients with a PD-L1 expression of less than1%, the median PFS was 7.6 months in arm A, 7.4 months in arm B, and 5.5 months in arm C. In those with PD-L1 expression ranging from 1% to 49%, the median PFS was 7.6 months in arm A, not evaluable in arm B, and 4.2 months in arm C. In patients with a PD-L1 expression of greater than 50%, the median PFS was 7.6 months in arm A, 7.6 months in arm B, and 5.5 months in arm C.

With regard to responses, the ORR was 73% in arm A, 75% in arm B, and 50% in arm C. The ORR in arm A included a 4% CR rate and a 68% PR rate. The stable disease rate in arm A was 15%, with 10% of patients experiencing disease progression. The ORR in arm B included a 3% CR rate and a 72% PR rate. The stable disease rate in arm B was 16% with 4% of patients experiencing disease progression.

In another ongoing phase 2 trial (NCT03432598), investigators are examining the agent in combination with platinum-based chemotherapy as a frontline treatment for Chinese patients with advanced disease. In this trial, patients with nonsquamous disease were administered tislelizumab plus pemetrexed and platinum-based therapy followed by pemetrexed maintenance. Patients with squamous disease were given the PD-1 inhibitor combined with paclitaxel and platinum-based therapy or with gemcitabine and platinum-based therapy. Patients with small cell lung cancer were administered the agent in combination with etoposide and platinum-based therapy.

As of October 15, 2018, a total of 54 patients had been administered tislelizumab; 24 of these patients remained on treatment. Preliminary results demonstrated that the ORR with the agent was 67%, which included 36 partial responses (PRs). The majority of the PRs were experienced within the first 2 assessments.⁴ A total of 13 patients achieved stable disease, 2 experienced disease progression, and 3 missed their first assessment.

The ORR was 44% in the nonsquamous (n = 16) group who received tislelizumab, 80% in the squamous group who received the PD-1 inhibitor with paclitaxel and platinum-based therapy (n = 15), and 77% in the squamous group who were administered tislelizumab combined with gemcitabine and platinum-based therapy (n = 6).

With regard to safety, grade ≥3 events reported in >15% of patients included decreased neutrophil counts (n = 25) and anemia (n = 9). Immune-related events reported with the PD-1 inhibitor were decreased triiodothyronine, hyperthyroidism, hypothyroidism, and pyrexia (n = 2, each). One patient with squamous disease had fatal myocarditis/myositis after receiving just 1 treatment cycle. Other toxicities resolved by interrupting treatment (n = 30), discontinuing treatment (n = 4), or through the use of other appropriate treatment.

Tislelizumab is currently approved for use in China as an option for patients with classical Hodgkin lymphoma who had been given at least 2 prior therapies. The agent is also indicated for patients with locally advanced or metastatic urothelial carcinoma with PD-L1–high expression whose disease progressed either during or following treatment with a platinum-based chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment with a platinum-based chemotherapy.

“Together with the previously accepted filing in patients with squamous histology, we look forward to continuing our dialogue with the Center for Drug Evaluation and to hope to bring this innovative treatment to hundreds of thousands of Chinese patients and families impacted by this devastating disease every year,” said Wu.

References:

1. BeiGene announces acceptance of a supplemental new drug application for tislelizumab in combination with chemotherapy in first-line advanced non-squamous non-small cell lung cancer in China. News release. June 19, 2020. Accessed June 22, 2020. bit.ly/3dn93ol.
2. Wang J, Yu X, Hu Y, et al. Phase III study of tislelizumab plus chemotherapy vs chemotherapy alone as first-line (1L) treatment for advanced squamous non-small cell lung cancer (sq NSCLC). J Clin Oncol. 2020;38(suppl 15):9554. doi:10.1200/JCO.2020.38.15_suppl.9554
3. BeiGene announces that the phase 3 clinical trial of its anti-pd-1 antibody tislelizumab in patients with first-line squamous non-small cell lung cancer met the primary endpoint of progression-free survival at interim analysis. News release. January 21, 2020. Accessed June 22, 2020. yhoo.it/38q8ubb.
4. Wang J, Zhao J, Wang Z, et al. Tislelizumab, an investigational anti-PD-1 antibody, combined with chemotherapy as first-line treatment for lung cancer in Chinese patients. J Clin Oncol. 2019;37(suppl_15): doi: 10.1200/JCO.2019.37.15_suppl.e14067