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KEYNOTE-042: Pembrolizumab monotherapy works in PD-L1–positive advanced NSCLC regardless of STK11 or KEAP1 status

Dr Margaret Shi
14 May 2020

Pembrolizumab monotherapy improves overall survival (OS) and cancer control compared with platinum-based chemotherapy in patients with untreated locally advanced or metastatic programmed death-ligand 1 (PD-L1)–positive non-small-cell lung cancer (NSCLC) regardless of STK11 or KEAP1 mutation status, according to results of the phase III KEYNOTE-042 study.

“Pembrolizumab should be considered as a standard first-line treatment option for advanced PD-L1– positive NSCLC regardless of STK11 or KEAP-1 mutation status,” said investigator Dr Byoung Chul Cho from the Yonsei University, Seoul, South Korea. [Cho BC, et al, AACR 2020, abstract CT084]

In the trial, 1,274 patients (median age, 63 years; male, 70.8 percent) with untreated locally advanced or metastatic NSCLC without sensitizing EGFR mutation or ALK translocation, who had PD-L1 tumour proportion score (TPS) 1 percent, were randomized (1:1) to receive pembrolizumab (200 mg Q3W for up to 35 cycles) or chemotherapy (carboplatin plus paclitaxel or carboplatin plus pemetrexed) for up to 6 cycles.

Matched germline DNA and evaluable data for STK11 and KEAP1 mutation were available for 33.7 percent of all randomized participants, in which 53.6 percent of patients in the mutation-evaluable group received pembrolizumab monotherapy.

At baseline, the proportion of patients with PD-L1 TPS of 1–49 percent was similar between the mutation-evaluable population and the total population (54.3 percent vs 53.0 percent).

Comparable outcomes of OS, progression-free survival (PFS) and objective response rate (ORR) with pembrolizumab vs chemotherapy were achieved between the mutation-evaluable population (OS hazard ratio [HR], 0.77; 95 percent confidence interval [CI], 0.62 to 0.97) (PFS HR, 0.90; 95 percent CI, 0.73 to 1.10) (ORR, 29.6 percent vs 22.1 percent) and the total population (OS HR, 0.82; 95 percent CI, 0.71 to 0.93) (PFS HR, 1.05; 95 percent CI, 0.93 to 1.19) (ORR, 27.2 percent vs 26.5 percent).

STK11, KEAP1 and STK11/KEAP1 mutations were present in 7.7 percent, 14.9 percent and 2.8 percent of patients in the mutation-evaluable population, respectively.

Patients with vs without STK11 mutation had lower PD-L1 expression but higher tissue tumour mutational burden (tTMB) (median TPS, 15 percent vs 40 percent) (median tTMB score, 191 vs 146). Patients with vs without KEAP1 mutation had similar levels of PD-L1 expression but higher tTMB (median TPS, 40 percent vs 40 percent) (median tTMB score, 183 vs 142).

In this exploratory analysis, significant improvement in OS was demonstrated with pembrolizumab vs chemotherapy among patients with or without STK11 or KEAP1 mutation (STK11 mut: HR, 0.37; 95 percent CI, 0.16 to 0.86) (STK11 wt: HR, 0.83; 95 percent CI, 0.65 to 1.05) (KEAP1 mut: HR, 0.75; 95 percent CI, 0.42 to 1.35) (KEAP1 wt: HR, 0.78; 95 percent CI, 0.61 to 0.99).

A comparable numerical improvement in PFS with pembrolizumab vs chemotherapy was seen among patients with or without STK11 and KEAP1 mutations (STK11 mut: HR, 0.75; 95 percent CI, 0.36 to 1.57) (STK11 wt: HR, 0.91; 95 percent CI, 0.74 to 1.13) (KEAP1 mut: HR, 0.67; 95 percent CI, 0.38 to 1.17) (KEAP1 wt: HR, 0.96; 95 percent CI, 0.77 to 1.20).

The ORR was 31.3 percent vs 5.9 percent and 29.4 percent vs 23.6 percent with pembrolizumab vs chemotherapy among patients with and without STK11 mutation. Similar ORRs were reported among patients with and without KEAP1 mutation (35.5 percent vs 18.2 percent and 28.6 percent vs 22.9 percent, respectively). 
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