The China National Medical Products Administration has accepted a supplemental new drug application for the PD-1 inhibitor tislelizumab for use in combination with chemotherapy for the first-line treatment of patients with advanced squamous non–small cell lung cancer.
The China National Medical Products Administration has accepted a supplemental new drug application (sNDA) for the PD-1 inhibitor tislelizumab for use in combination with chemotherapy for the first-line treatment of patients with advanced squamous non—small cell lung cancer (NSCLC).1
The sNDA is based on data from the phase 3 BGB-A317-307 trial (NCT03594747), which showed that tislelizumab in combination with chemotherapy improved progression-free survival (PFS) compared with chemotherapy alone as a first-line treatment for patients with advanced squamous NSCLC. The results came from an interim analysis conducted by an independent review committee (IRC) showing that tislelizumab in combination with either carboplatin/paclitaxel or with carboplatin/nab-paclitaxel (Abraxane) crossed the prespecified efficacy boundary compared with carboplatin/paclitaxel alone.
Regarding safety, the safety profile for tislelizumab with either chemotherapy regimen was found to be consistent with the known risks of each study treatment and no new safety signals were identified. Full findings from the study will be presented at an upcoming medical meeting, according to BeiGene, the developer of tislelizumab.
“This sNDA filing is another important milestone in tislelizumab’s development program, coming on the heels of its recent approval in urothelial carcinoma in China — our first approval in solid tumors and the announcement of the positive outcome of our second study in first-line NSCLC, in patients with non-squamous histology. Our team was able to submit the regulatory application only 20 months after trial initiation, illustrating how efficiently we can move to serve those in need,” Xiaobin Wu, PhD, general manager of China and President of BeiGene, said in the press release. “We look forward to working closely with the CDE on this filing and hope to bring a new treatment option to the large population of patients with advanced squamous NSCLC in China who could benefit from immunotherapy.”
In the multicenter, open-label, randomized, phase III BGB-A317-307 trial, the efficacy and safety of tislelizumab combined with either carboplatin/paclitaxel or carboplatin/nab-paclitaxel was compared with carboplatin/paclitaxel alone in 360 patients from mainland China with untreated stage IIIb/IV squamous NSCLC, regardless of PD-L1 expression. Patients were randomized in a 1:1:1 fashion and tislelizumab was administered at 200 mg every 3 weeks in combination with the chemotherapy regimens until disease progression, unacceptable toxicity, physician consent, or withdrawal.
Patients who were on the chemotherapy-only arm and experienced disease progression, verified by central independent review, were permitted to cross over to receive single-agent tislelizumab.
To be eligible for enrollment, patients must have been between 18 and 75 years old, had advanced NSCLC with squamous histology, an ECOG performance status ≤1, at least 1 measurable lesion, did not previously receive treatment for locally advanced or metastatic squamous disease, had a life expectancy ≥12 weeks, and had adequate organ function. Patients could not have a history of interstitial lung disease, HIV infection, active or a history of autoimmune disease, clinically significant pericardial effusion, or have had severe infections, active leptomeningeal disease, or uncontrolled or untreated brain metastasis. Moreover, patients could not have EGFR or ALK abnormalities, nor could they have received prior systemic treatment with EGFR, ALK, or PD-1/PD-L1 inhibitors.
The primary endpoint is PFS per IRC; key secondary endpoints include objective response rate (ORR), duration of response, overall survival, and safety.
An ongoing phase II trial is evaluating tislelizumab with platinum-based chemotherapy as a first-line treatment for Chinese patients with advanced lung cancer (NCT03432598). Patients with nonsquamous disease received tislelizumab with pemetrexed plus platinum-based therapy followed by pemetrexed maintenance; those with squamous disease received tislelizumab with paclitaxel/platinum-based therapy or with gemcitabine/platinum-based therapy. Patients with small cell lung cancer (SCLC) received tislelizumab with etoposide and platinum-based therapy.
As of October 15, 2018, 54 patients had received tislelizumab and 24 remained on treatment. Preliminary data showed that the ORR was 67%, which comprised 36 partial responses, most of which occurred within the first 2 assessments.2 Thirteen patients had stable disease, 2 had progressive disease, and 3 missed their first assessment. In the nonsquamous (n = 16), squamous with paclitaxel/platinum-based therapy (n = 15), squamous with gemcitabine/platinum-based therapy (n = 6), and SCLC (n = 17) groups, the ORRs were 44%, 80%, 67%, and 77%, respectively.
Additionally, grade ≥3 adverse events (AEs) occurring in >15% of patients included decreased neutrophil counts (n = 25) and anemia (n = 9). Immune-related AEs, which occurred in ≥2 patients, included decreased triiodothyronine, hyperthyroidism, hypothyroidism, and pyrexia (n = 2 each). There was 1 patient with squamous NSCLC who experienced fatal myocarditis/myositis after 1 cycle of treatment. However, other AEs resolved with interruption of tislelizumab (n = 30), discontinuation (n = 4), or other appropriate treatment.
Currently, tislelizumab is approved by the China NMPA as a treatment for patients with classical Hodgkin lymphoma who received ≥2 prior therapies. Moreover, the drug is also approved for use in patients with previously treated locally advanced or metastatic urothelial carcinoma.
Tislelizumab is a humanized IgG4 PD-1-directed monoclonal antibody specifically designed to minimize binding to FcγR on macrophages, BeiGene stated in the press release. The company added that preclinical data have shown that binding to FcγR on macrophages compromises the antitumor activity of PD-1 antibodies through activation of antibody-dependent macrophage-mediated killing of T-effector cells.