Pembrolizumab + chemotherapy beneficial in advanced NSCLC, even without PD-L1 expression

Previous research has shown that frontline treatment with pembrolizumab + platinum-based chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC; squamous or non-squamous without epidermal growth factor receptor [EGFR]/anaplastic lymphoma kinase [ALK] mutation) irrespective of PD-L1 expression improves clinical outcomes when compared to standard chemotherapy alone[1-3]. However, more knowledge and insights are required with regard to outcomes for pembrolizumab + chemotherapy in patients without PD-L1 expression as these patients are not eligible for treatment with pembrolizumab monotherapy.

Borghaei et al. aimed to put together a pooled analysis of pembrolizumab + chemotherapy in patients with advanced/metastasised NSCLC without PD-L1 expression (tumour proportion score [TPS] <1%) which was based on 3 randomised trials: KEYNOTE-021, KEYNOTE-189, and KEYNOTE 407 [4-6]. These 3 studies held a total of 1,298 patients. Of those, 33.0% had a PD-L1 TPS <1%; 243 patients received pembrolizumab + chemotherapy and 185 received platinum-based chemotherapy. Both groups had similar baseline characteristics with the exception of squamous histology (this concerned 39% of patients in the combination arm and 54% of patients in the chemotherapy arm) and liver metastases which were seen in 16% and 23%, respectively.

Combining pembrolizumab + chemotherapy was superior with regard to overall survival (OS) in this patient population when compared with chemotherapy [7]. Median OS was 19 months (15.2-24.0 months) vs 11 months (9.2-13.5 months; HR 0.56, 95% CI 0.43-0.73). The OS benefit was consistent in every analysed subgroup. These were: age at cut-off 65 years; sex; region of inclusion (eastern Asia or the rest of the world); ECOG performance status 0 or 1; histology (squamous or non-squamous); smoking status; and the absence or presence of liver metastases and brain metastasis. Progression-free survival (PFS) was 6.5 months (6.2-8.5 months) for patients who were treated with the combination of pembrolizumab + chemotherapy compared with 5.4 months (4.7-6.2 months) for those receiving chemotherapy (HR 0.67, 95% CI 0.54-0.84). Also, the proportion of patients who achieved an objective response rate (ORR) was higher with 46.9% for combination therapy vs 28.6% for chemotherapy (the estimated difference was 18.3% [95% CI 9.0-27.1] and the number of patients which was still being treated at 12 months was higher in the combination group (42.4% vs 35.3%).

Treatment-related adverse events (AEs) were similar to what had been observed before. Patients who were treated with the combination of pembrolizumab + chemotherapy experienced immune-related AEs more frequently than those on chemotherapy monotherapy (26% vs 12%, respectively). Of those, 11% and 3% were grade 3-5. It was concluded that the safety profile of the combination is manageable.

Based on these findings the first-line combination of pembrolizumab + chemotherapy should be considered standard of care in patients with advanced squamous or non-squamous NSCLC, including patients with PD-L1-negative tumours. [7].

1. Langer CJ, et al. Lancet Oncol. 2016;17(11);1497-1508.
2. Borghaei H, et al. J Thoracic Oncol. 2019;14(1):124-129.
3. Ghandi L, et al. N Eng J Med. 2018;378(22):2078-2092.
4. Gadgeel SM, et al. J Clin Oncol. 2019;37(15):9013.
5. Paz-Ares LG, et al. N Engl J Med. 2018; 379:2040-2051.
6. Paz-Ares LG, et al. J Clin Oncol. 2018;36(suppl): Abstract 105.
7. Borghaei H, et al. MA25.01. WCLC 2019.

Posted on 8 November 20195 March 2021