Current status of first‐line treatment with pembrolizumab for non–small‐cell lung cancer with high PD‐L1 expression

Abstract It is not clear whether pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum‐based chemotherapy (COMB) should be selected for patients with advanced non–small‐cell lung cancer (NSCLC) exhibiting high PD‐L1 expression (tumor proportion score ≥ 50%). We performed a retrospective, multicenter study of 300 patients with NSCLC exhibiting high PD‐L1 expression who received MONO or COMB as first‐line treatment between December 2018 and January 2020. We reviewed the medical records of all consecutive patients with no driver mutations, and assessed the patient characteristics, therapeutic regimens, treatment periods, and adverse events. In total, 166 (55%; median age: 74 years) and 134 (45%; median age: 68 years) patients received MONO and COMB, respectively. Patients were younger and had better performance status (0–1) in the COMB group (p < 0.01). With a median follow‐up time of 10.6 (range: 0.1–20.6) months, the median progression‐free survival was 7.1 months with MONO and 13.1 months with COMB. The objective response rate was 42.2% with MONO and 67.9% with COMB. With respect to treatment discontinuation, 36 out of 166 (21.7%) and 28 out of 134 (20.1%) patients discontinued MONO and COMB, respectively. In conclusion, COMB may be a promising option for first‐line treatment for NSCLC with high PD‐L1 expression and good performance status.


| INTRODUC TI ON
Recently, PD-1/PD-L1 inhibitors have shown efficacy against advanced NSCLC; therefore, they have emerged as standard therapies for patients with advanced-stage disease.
Pembrolizumab monotherapy (MONO) for advanced NSCLC with high PD-L1 expression (PD-L1 tumor proportion score [TPS] ≥ 50%) was approved as a first-line therapy based on the results of previous studies. 1,2 In the phase III randomized KEYNOTE-024 trial, MONO was shown to prolong PFS and OS compared with platinumbased chemotherapy alone. 1 Furthermore, in the subgroup population expressing high levels of PD-L1 in the phase III randomized KEYNOTE-042 trial, MONO was shown to prolong PFS and improve OS compared with platinum-based chemotherapy alone, as noted in the KEYNOTE-024 report. 2 Thereafter, in two other phase III trials (KEYNOTE-189 and KEYNOTE-407), pembrolizumab plus platinum-based chemotherapy (COMB) was established as a firstline treatment for patients with advanced NSCLC, regardless of PD-L1 expression level, compared with platinum-based chemotherapy alone. In particular, COMB was more effective for both PFS and OS in patients with high PD-L1 expression compared with platinumbased chemotherapy. 3,4 These clinical trials and some meta-analyses support the notion that MONO and COMB are beneficial as first-line treatments for advanced NSCLC with high PD-L1 expression. [5][6][7] In terms of AEs, these studies suggest that there may be a lower incidence of treatment-related AEs of both all grades and grades [3][4][5] in patients who received MONO compared with COMB. It is recognized that MONO is better tolerated than COMB. [1][2][3][4] Based on limited data, the selection of MONO or COMB for patients with high PD-L1 expression is a major issue in clinical practice. Therefore, we retrospectively analyzed the data of patients with NSCLC with high PD-L1 expression who received MONO or COMB in clinical practice. We aimed to understand the current status of treatment with pembrolizumab in clinical practice, and to conduct statistical analysis to help in selecting appropriate treatment for patients with high PD-L1 expression.

| Study population and design
This study (HOT/NJLCG2001) was performed with a retrospective, multicenter, observational design to evaluate the efficacy and toxicity of MONO or COMB as first-line treatments between December 2018 and January 2020. We reviewed the medical records of all consecutive patients with advanced or recurrent NSCLC with high PD-L1 expression (TPS ≥ 50%) and no documented EGFR, ALK, or ROS1 aberrations who were treated with MONO or COMB in 34 institutions that belong to Hokkaido Lung Cancer Clinical Study Group HOT, North Japan Lung Cancer Study Group (NJLCG) in Japan. The data cutoff was August 31, 2020. This study was approved by the institutional review boards of all institutions, which also waived the need to obtain informed consent because the data were analyzed anonymously.

| Data collection
We assessed the characteristics of the patients, therapeutic regimens, treatment period, and AEs. We recorded the patients' age, sex, smoking status, histology, cancer stage, PD-L1 status, and the Eastern Cooperative Oncology Group performance status (ECOG PS) at the start of initial treatment. We recorded therapeutic with NSCLC exhibiting high PD-L1 expression who received MONO or COMB as firstline treatment between December 2018 and January 2020. We reviewed the medical records of all consecutive patients with no driver mutations, and assessed the patient characteristics, therapeutic regimens, treatment periods, and adverse events. In total, 166 (55%; median age: 74 years) and 134 (45%; median age: 68 years) patients received MONO and COMB, respectively. Patients were younger and had better performance status (0-1) in the COMB group (p < 0.01). With a median follow-up time of 10.6 (range: 0.1-20.6) months, the median progression-free survival was 7.1 months with MONO and 13.1 months with COMB. The objective response rate was 42.2% with MONO and 67.9% with COMB. With respect to treatment discontinuation, 36 out of 166 (21.7%) and 28 out of 134 (20.1%) patients discontinued MONO and COMB, respectively. In conclusion, COMB may be a promising option for first-line treatment for NSCLC with high PD-L1 expression and good performance status.

K E Y W O R D S
combination chemotherapy, non-small-cell lung cancer, PD-L1 inhibitor, pembrolizumab, retrospective study regimens (MONO or COMB) and the kind of COMB (carboplatin/cisplatin + pemetrexed, carboplatin + (nab-)paclitaxel). We extracted AE types of grade ≥3 and AE types leading to treatment discontinuation using common terminology criteria for AEs (CTCAE v.5.0). 8 Tumor response was measured using RECIST version 1.1. 9 Because of the retrospective study design, CR and PR did not need confirmation. Assessments were performed in each participating institution.
The baseline patient characteristics are summarized in Table 1

| Safety and toxicity
b Excluding cases whose PD-L1 status is unknown.

| Propensity score matching analysis
To control the unbalanced conditions at baseline between the groups, we used PSM with age and PS as adjustment factors and the 1:1 matching yielded match pairs of 84 patients in the two groups, resulting in no differences in any of the characteristics ( Figure S1 and Table S1). The median PFS duration was 9.  In multivariate regression analyses, two independent factors were identified as good PFS factors: PS 0-1 and PD-L1 ≥90% (Table 4).

| DISCUSS ION
In this retrospective multicenter observational study for advanced NSCLC with high PD-L1 expression, we found that COMB was associated with a longer PFS and higher ORR compared with MONO in clinical practice. The discontinuation rates due to AEs were also similar in both groups. Furthermore, using PSM, we found that the median PFS and OS of COMB showed a trend toward better than MONO, although they were not statistically significant. Based on our results, we suggest

F I G U R E 4
Kaplan-Meier curves of progression-free survival of patients receiving pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum-based chemotherapy (COMB) according to a PD-L1 tumor proportion score of (A) 50%-89%, (B) ≥90%. mo, month; PFS, progression-free survival studies, the incidence of AEs associated with treatment discontinuation was higher in both COMB and MONO.   Kobayashi (Okaya City Hospital) for proofreading the manuscript.

D I SCLOS U R E
The authors have no conflict of interest.

E TH I C A L CO N S I D ER ATI O N S
All procedures performed were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study was approved by the institutional review boards of all participating institutions (clinical trial registration no.