Tislelizumab-chemo a suitable first-line treatment alternative for advanced sq-NSCLC?

The addition of the monoclonal antibody tislelizumab to chemotherapy (CT) offers superior clinical benefit over CT alone as reflected by the prolonged progression-free survival (PFS), higher objective response rate (ORR), and a manageable safety and tolerability profile, underlining the potential of the combo regimen as a first-line treatment alternative for individuals with advanced squamous non-small-cell lung cancer (sq-NSCLC), the RATIONALE 307 trial suggests.

Most sq-NSCLC cases are diagnosed at an advanced stage, thus confounding disease management. [J Thorac Oncol 2018;13:165-183] “Prognosis has been poor for patients treated with standard platinum-based CT, highlighting a high unmet medical need,” said the researchers.

Evidence shows that combining standard first-line treatments with anti-PD-1/L1 monoclonal antibodies has shown potential for NSCLC treatment. [Nat Rev Clin Oncol 2019;16:79-80; Lancet Oncol 2019;20:924-937] “[However,] to our knowledge, pembrolizumab plus standard CT is the only approved treatment for advanced sq-NSCLC … [As such,] further investigation into the combination of a PD-1/L1 inhibitor plus CT is warranted,” they continued.

The team evaluated 355 patients with treatment-naïve, histologically confirmed stage IIIB/IV sq-NSCLC (median age 62 years, 92 percent male). Participants were randomized 1:1:1 to receive one of three IV regimens Q3W: tislelizumab 200 mg plus CT comprising paclitaxel 175 mg/m² and carboplatin (all administered on day 1; arm A), tislelizumab plus CT comprising nab-paclitaxel 100 mg/m² (days 1, 8, and 15) and carboplatin (arm B), and CT alone (paclitaxel-carboplatin; arm C). [JAMA Oncol 2021;7:709-717]

Compared with arm C, IRC*-assessed PFS was significantly improved in arm A (7.6 months vs 5.5 months; hazard ratio [HR], 0.52) and arm B (7.6 months vs 5.5 months; HR, 0.48; p<0.001 for both) after a median follow-up of 8.6 months.

Subgroup analyses also favoured tislelizumab-CT over CT alone in terms of median PFS, be it among those with stage IIIB (9.8 vs 5.6 months; HR, 0.40 [arm A vs C] and 11.0 vs 5.6 months; HR, 0.37 [arm B vs C]) or stage IV disease (7.6 vs 5.2 months; HR, 0.57 and 7.4 vs 5.2 months; HR, 0.54, respectively).

“[The comparable results] suggest that patients with stage IIIB and IV disease have similar clinical prognosis,” the researchers explained. Moreover, the PFS benefit seen in individuals with stage IIIB disease indicate a potential new treatment option for this patient subgroup. The prolonged PFS among those with stage IV disease align with those observed in KEYNOTE-407 and IMpower131. [N Engl J Med 2018;379:2040-2051; J Thorac Oncol 2020;15:1351-1360]

Arms A and B also had higher IRC-assessed ORRs than arm C (73 percent and 75 percent vs 50 percent) and longer median duration of response (DoR; 8.2 and 8.6 months vs 4.2 months). “[The] observed responses were clinically meaningful and durable, with a doubling of DoR by >4 months vs CT alone,” said the researchers.

Treatment discontinuation rates owing to adverse events (AEs) were 12, 30, and 15 percent in the respective arms A, B, and C. The higher rate in arm B may have been driven by the more frequent administration and safety evaluations with nab-paclitaxel vs paclitaxel, the researchers explained.

Treatment-emergent AEs leading to permanent discontinuation of tislelizumab were similar in arms A and B (10 percent in both arms). Hypothyroidism, pneumonia, and hyperglycaemia were the most frequent potential immune-mediated AEs tied to tislelizumab. However, most were low grade and did not lead to treatment withdrawal. The six treatment-related AEs leading to death were not solely attributed to tislelizumab.

“[In our study,] the addition of tislelizumab to standard CT demonstrated a significant reduction to the risk of progression or death for patients with advanced sq-NSCLC … who are not amenable to curative surgery or chemoradiotherapy … This represents an additional treatment option as first-line treatment for patients with sq-NSCLC,” said the researchers.