Pembrolizumab plus chemotherapy in Japanese patients with metastatic squamous non-small-cell lung cancer in KEYNOTE-407

Abstract

The global phase III KEYNOTE-407 (NCT02775435) trial showed that pembrolizumab plus chemotherapy prolonged overall and progression-free survival (OS/PFS) versus placebo plus chemotherapy in patients with metastatic squamous non-small-cell lung cancer (NSCLC). We present outcomes of patients from Japan enrolled in KEYNOTE-407. Patients were randomized 1:1 to receive pembrolizumab 200 mg or placebo with paclitaxel 200 mg/m² every 3 weeks (Q3W) or nab-paclitaxel 100 mg/m² (weekly) plus carboplatin area under the concentration-time curve of 6 mg/mL/min Q3W for four cycles, followed by pembrolizumab or placebo Q3W for a total of 35 cycles. Primary end-points were OS and PFS per RECIST version 1.1 by blinded independent central review. Fifty patients were randomized at Japanese sites (pembrolizumab plus chemotherapy, n = 22; placebo plus chemotherapy, n = 28). Median follow-up time at data cut-off (May 9, 2019) was 15.1 (range, 0.5–24.0) months. Median OS (95% confidence interval [CI]) was 17.3 (12.5–not reached) versus 11.0 (8.6–19.5) months in the pembrolizumab plus chemotherapy versus placebo plus chemotherapy group (hazard ratio [HR] 0.56; 95% CI, 0.27–1.15). Median PFS (95% CI) was 8.3 (6.1–13.0) versus 7.2 (3.9–8.8) months (HR 0.65; 95% CI, 0.35–1.23). Grade 3–5 adverse events (AEs) occurred in 86% and 75% of patients, respectively. There were three fatal AEs, two of which were treatment-related (one from each treatment group, pneumonitis and pulmonary hemorrhage). Efficacy and safety outcomes were consistent with the global study and support the use of pembrolizumab plus chemotherapy in Japanese patients with metastatic squamous NSCLC.

Abbreviations
• AE
• adverse event
• BICR
• blinded independent central review
• CI
• confidence interval
• CT
• computed tomography
• CTCAE
• Common Terminology Criteria for Adverse Events
• DOR
• duration of response
• ECOG
• eastern cooperative oncology group
• HR
• hazard ratio
• mAb
• monoclonal antibody
• NSCLC
• non-small-cell lung cancer
• ORR
• objective response rate
• OS
• overall survival
• PD-1
• programmed death 1
• PD-L1
• programmed death ligand 1
• PFS
• progression-free survival
• PFS2
• progression-free survival in the second line
• Q3W
• every 3 weeks
• TPS
• tumor proportion score

INTRODUCTION

Lung cancer had the highest mortality of all cancers in Japan in 2020.¹ For NSCLC, the Japanese Lung Cancer Society guidelines recommend monotherapy with pembrolizumab, a humanized mAb against PD-1, or platinum-containing chemotherapy plus a PD-1 or PD-L1 inhibitor, as first-line treatment in patients with stage 4 NSCLC with PD-L1 TPS ≥50% with no EGFR/ALK alterations.² For a subset of patients (those without a driver oncogene and with PD-L1 TPS <50% or unknown status), the first-line treatment recommendation is for platinum-containing chemotherapy plus a PD-(L)1 inhibitor.² These recommendations include pembrolizumab as part of the chemotherapy-combination treatment regimen and are based, in part, on phase III studies demonstrating significantly prolonged PFS and OS with pembrolizumab plus platinum-based chemotherapy compared with placebo plus platinum-based chemotherapy.^2–4

One of these studies included KEYNOTE-407, a global, randomized, double-blind, placebo-controlled phase III trial of pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel (chemotherapy) compared with placebo plus chemotherapy as first-line treatment for metastatic squamous NSCLC.³ In the primary analysis of KEYNOTE-407, pembrolizumab plus chemotherapy significantly prolonged OS (HR 0.64; 95% CI, 0.49–0.85; p < 0.001) and PFS (HR 0.56; 95% CI, 0.45–0.70; p < 0.001) versus placebo plus chemotherapy.³ These trends were maintained in the protocol-specified final analysis of this study (HR for OS 0.71; 95% CI, 0.58–0.88; HR for PFS 0.57; 95% CI, 0.47–0.69).⁵

Historically, disease characteristics in Asian patients with NSCLC, their response to treatment, associated outcomes, and severity of toxicity can differ from Caucasian and/or non-Asian patients.^6,7 In addition, Asian patients are generally underrepresented in large global studies, and there are limited studies to date that have evaluated outcomes of immune checkpoint inhibitors specifically in Asian patients.⁸ To help address this gap, we report the efficacy and safety outcomes of pembrolizumab plus chemotherapy compared with placebo plus chemotherapy in patients with previously untreated metastatic squamous NSCLC enrolled in Japan in the KEYNOTE-407 study.

MATERIALS AND METHODS Study design and patients

The phase III KEYNOTE-407 (NCT02775435) study design has been previously described.^3,5 Patients included in this subgroup analysis of KEYNOTE-407 were enrolled in Japan. Briefly, patients aged 18 years or older with a histologically or cytologically confirmed diagnosis of stage IV squamous NSCLC who had not received previous systemic treatment for metastatic NSCLC were enrolled. Eligible patients had measurable disease based on RECIST version 1.1, an ECOG performance status of 0 or 1, life expectancy of more than 3 months, and adequate organ function and were required to provide tumor tissue for assessment of PD-L1 status. Patients were excluded if they had major surgery less than 3 weeks before first dose, received radiation therapy to the lung that was more than 30 Gy within 6 months of first dose, completed palliative radiotherapy within 7 days before study treatment, received live-virus vaccine within 30 days, had a history of previous malignancy, had active central nervous system metastases and/or carcinomatous meningitis, had peripheral neuropathy grade 2 or higher per NCI CTCAE version 4, had prior treatment with any other anti-PD-1, -PD-L1, or -PD-L2 agent, had active autoimmune disease that required systemic therapy in the past 2 years, were taking long-term systemic steroids, or had interstitial lung disease or history of pneumonitis that required steroid therapy.

Patients were randomized 1:1 to receive either pembrolizumab 200 mg i.v. or saline placebo Q3W with paclitaxel 200 mg/m² Q3W or nab-paclitaxel 100 mg/m² weekly plus carboplatin area under the concentration-time curve of 6 mg/mL/min Q3W for four cycles, followed by pembrolizumab 200 mg or placebo Q3W, for a total of 35 cycles. Treatment continued until completion of 35 cycles, radiographic disease progression, patient withdrawal of consent, investigator's decision, or discontinuation due to unacceptable toxicity. Additionally, patients in the pembrolizumab plus chemotherapy group who experienced clinical benefit despite confirmed radiographic disease progression and no increased tumor burden were permitted to continue open-label pembrolizumab monotherapy. Patients in the placebo plus chemotherapy group with confirmed disease progression were permitted to cross over to receive pembrolizumab monotherapy if all eligibility criteria were met. Randomization was stratified by PD-L1 TPS (≥1% vs. <1%), choice of taxane chemotherapy (paclitaxel vs. nab-paclitaxel), and geographic region (East Asia vs. non–East Asia).

The trial was carried out in compliance with local and/or national regulations and in accordance with the ethical principles outlined in the Declaration of Helsinki. All procedures were approved by the appropriate institutional review board or ethics committee. All patients provided written informed consent before enrollment.

End-points

The dual primary end-points were OS (time from randomization to death due to any cause) and PFS (time from randomization to first of disease progression per RECIST version 1.1⁹ by BICR or death due to any cause). The secondary end-points were ORR (proportion of patients who have a complete response or partial response per RECIST version 1.1 by BICR), DOR, and safety and tolerability. Exploratory objectives included PFS2, defined as the time from randomization to subsequent disease progression (per RECIST version 1.1 assessed by the investigator) after initiation of new anticancer treatment or death from any cause.

Assessments

Expression of PD-L1 in tumor samples was assessed centrally using PD-L1 IHC 223C pharmDx (Agilent Technologies, Carpinteria, CA) prior to randomization. Baseline tumor imaging was undertaken within 28 days before initiating study treatment, with subsequent imaging occurring at week 6, 12, and 18, and then every 9 weeks until week 45, and every 12 weeks thereafter. Among patients who crossed over from placebo to receive pembrolizumab, tumor response was assessed every 12 weeks until initiation of another anticancer treatment. AEs were monitored throughout study treatment and for 30 days after the end of study treatment (90 days for serious AEs) and graded according to NCI CTCAE version 4.03.

Statistical analysis

Efficacy analysis was carried out in the intent-to-treat population. Overall survival, PFS, PFS2, and DOR were estimated within each treatment group using the nonparametric Kaplan–Meier method. The magnitude of treatment differences (HR and 95% CI) was assessed using a Cox proportional hazards model with the Efron method of tie handling. The ORR difference between groups was also estimated. Safety analysis was carried out in all patients as treated who received at least one dose of study treatment. These analyses in the Japanese population were post hoc and descriptive and no statistical tests were performed.

RESULTS Patients and treatment

Among 559 patients randomized in the KEYNOTE-407 global study (pembrolizumab plus chemotherapy, n = 278; placebo plus chemotherapy, n = 281), 50 patients (pembrolizumab plus chemotherapy, n = 22; placebo plus chemotherapy, n = 28) were randomized at 24 Japanese sites between April 2017 and November 2017. All patients received treatment as assigned (Figure 1). Baseline characteristics were similar between the two treatment groups. The median (range) age was 69.5 (45–87) years in the pembrolizumab plus chemotherapy group and 69.0 (43–82) years in the placebo plus chemotherapy group (Table 1). A majority of patients were men (86% in both treatment groups) and received nab-paclitaxel (86% in the pembrolizumab plus chemotherapy group vs. 79% in the placebo plus chemotherapy group). Among patients in the pembrolizumab plus chemotherapy group, 18% had PD-L1 TPS ≥50%, 32% had TPS 1%–49%, and 41% had TPS <1%. Among patients in the placebo plus chemotherapy group, 21%, 32%, and 46% had PD-L1 TPS ≥50%, 1%–49%, and <1%, respectively.

FIGURE 1. CONSORT flow diagram of Japanese patients enrolled in the KEYNOTE-407 study. PD-(L)1, programmed death 1 or programmed death ligand 1.

TABLE 1 Demographic and baseline clinical characteristics of Japanese patients enrolled in the KEYNOTE-407 study

Characteristica	Pembrolizumab + chemotherapy (n = 22)	Placebo + chemotherapy (n = 28)
Age, years; median (range)	69.5 (45–87)	69.0 (43–82)
Men	19 (86)	24 (86)
ECOG PS
0	10 (45)	13 (46)
1	12 (55)	15 (54)
Smoking status
Former/current	21 (95)	26 (93)
Never	1 (5)	2 (7)
Histology
Squamous	21 (95)	28 (100)
Otherb	1 (5)	0
Brain metastases	2 (9)	2 (7)
PD-L1 TPS
TPS < 1%	9 (41)	13 (46)
TPS ≥ 1%	11 (50)	15 (54)
TPS 1%–49%	7 (32)	9 (32)
TPS ≥ 50%	4 (18)	6 (21)
Unknown	2 (9)	0
Taxane chemotherapy
Paclitaxel	3 (14)	6 (21)
Nab-paclitaxel	19 (86)	22 (79)
Prior therapyc
Prior thoracic radiotherapy	0	2 (4)

Abbreviations: PD-L1, programmed death ligand 1; ECOG PS, Eastern Cooperative Oncology Group performance status; TPS tumor proportion score.

^aData are n (%) unless otherwise noted.

^bSMARCA 4-deficient sarcoma.

^cNo patient in either treatment group had received prior neoadjuvant or adjuvant therapy.

Median time from randomization to data cut-off (May 9, 2019) or death was 15.1 (range, 0.5–24.0) months. At data cut-off, 4 patients (18%) in the pembrolizumab plus chemotherapy group were receiving ongoing treatment, 18 (82%) had discontinued treatment (9 patients each due to radiographic progressive disease and AEs), and 11 (50%) received subsequent therapy. In the placebo plus chemotherapy group, 1 patient (4%) was receiving ongoing treatment, 27 (96%) had discontinued treatment (19 patients due to radiographic progressive disease, 3 patients each due to an AE or protocol-specified unblinding, and 2 due to clinical progression), and 22 (79%) received subsequent therapy (Figure 1, Table 2). Of the 11 patients in the pembrolizumab plus chemotherapy group, 4 (36%) received subsequent anti-PD-(L)1 therapy. Of the 22 patients in the placebo plus chemotherapy group, 16 (57%) received anti-PD-(L)1 therapy, including 8 (29%) who received pembrolizumab as part of the on-study cross-over (Figure 1).

TABLE 2 Subsequent antineoplastic therapies received off-study among Japanese patients enrolled in KEYNOTE-407^a

Therapy	Pembrolizumab + chemotherapy (n = 22)	Placebo + chemotherapy (n = 28)
Patients with ≥1 subsequent oncologic treatment(s)	11 (50)	19 (68)
Atezolizumab	1 (5)	0 (0)
Bevacizumab	1 (5)	0 (0)
Carboplatin	3 (14)	6 (21)
Cisplatin	1 (5)	1 (4)
Docetaxel	5 (23)	10 (36)
Gemcitabine	1 (5)	1 (4)
Gemcitabine hydrochloride	0 (0)	1 (4)
Gimeracil (+) oteracil potassium (+) tegafur	7 (32)	8 (29)
Nivolumab	3 (14)	7 (25)
Paclitaxel	0 (0)	1 (4)
Paclitaxel albumin	3 (14)	3 (11)
Pembrolizumab	1 (5)	2 (7)
Pemetrexed disodium	1 (5)	0 (0)
Ramucirumab	5 (23)	4 (14)
Vinorelbine tartrate	1 (5)	0 (0)
Strontium chloride Sr 89	0 (0)	1 (4)

^aDoes not include three patients in the placebo + chemotherapy group who received subsequent pembrolizumab monotherapy only as part of the on-study cross-over.

Efficacy outcomes

At the time of data cut-off, 12 patients (55%) in the pembrolizumab plus chemotherapy group and 19 (68%) in the placebo plus chemotherapy group had died. The median OS was 17.3 months (95% CI, 12.5 months–not evaluable) in the pembrolizumab plus chemotherapy group and 11.0 (95% CI, 8.6–19.5) months in the placebo plus chemotherapy group (HR, 0.56 [95% CI, 0.27–1.15]; Figure 2A). Estimated OS rates at 12 months were 77% in the pembrolizumab plus chemotherapy group and 49% in the placebo plus chemotherapy group.

FIGURE 2. Kaplan–Meier estimates of (A) overall survival and (B) progression-free survival per RECIST version 1.1 by blinded independent central review of Japanese patients enrolled in the KEYNOTE-407 study. Chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; mo, months; NR, not reached; Pembro, pembrolizumab.

A total of 16 events (73%) of disease progression or death had occurred in the pembrolizumab plus chemotherapy group compared with 24 (86%) in the placebo plus chemotherapy group at the time of data cut-off. The median PFS was 8.3 (95% CI, 6.1–13.0) months in the pembrolizumab plus chemotherapy group and 7.2 (95% CI, 3.9–8.8) months in the placebo plus chemotherapy group (HR 0.65 [95% CI, 0.35–1.23]; Figure 2B). Estimated PFS rates at 12 months were 39% in the pembrolizumab plus chemotherapy group and 19% in the placebo plus chemotherapy group.

The ORR was 68% (95% CI, 45%–86%) in the pembrolizumab plus chemotherapy group and 43% (95% CI, 24%–63%) in the placebo plus chemotherapy group (Table 3). One patient had complete response and 14 had partial response in the pembrolizumab plus chemotherapy group, whereas no patient had complete response and 12 had partial response in the placebo plus chemotherapy group (Figure 3). The median (range) DOR was 7.1 (1.3+ to 18.5) months and 5.7 (1.4+ to 20.2+) months, respectively (where “+” indicates no progressive disease by the time of last disease assessment). Based on Kaplan–Meier estimates, the DOR was ≥6 months for 63% of patients in the pembrolizumab plus chemotherapy group and 44% in the placebo plus chemotherapy group, and ≥12 months for 24% and 29%, respectively.

TABLE 3 An objective response per RECIST version 1.1 by blinded independent central review in Japanese patients enrolled in the KEYNOTE-407 study

	Pembrolizumab + chemotherapy (n = 22)	Placebo + chemotherapy (n = 28)
Objective response rate,a % (95% CI)	68 (45–86)	43 (24–63)
Best overall response, n (%)
Complete response	1 (5)	0 (0)
Partial response	14 (64)	12 (43)
Stable disease	6 (27)	12 (43)
Progressive disease	1 (5)	2 (7)
Not evaluableb	0 (0)	1 (4)
No assessmentc	0 (0)	1 (4)
Time to response, months; median (range)	1.4 (1.2–3.0)	1.5 (1.2–6.3)
DOR, months; median (range)	7.1 (1.3+ to 18.5)	5.7 (1.4+ to 20.2+)
Kaplan–Meier estimate of patients with extended DOR, n (%)
≥6 months	8 (63)	4 (44)
≥9 months	6 (48)	2 (29)
≥12 months	3 (24)	2 (29)

Note: +, no progressive disease by the time of last disease assessment.

Abbreviations: CI, confidence interval; DOR, duration of response.

^aObjective response rate comprised patients with complete response and partial response.

^bPostbaseline assessments available but not evaluable (including those with complete response/partial response/stable disease <6 weeks from randomization).

^cNo postbaseline assessment available for response evaluation.

FIGURE 3. Treatment duration and time to response in patients in the pembrolizumab plus chemotherapy group among Japanese patients enrolled in the KEYNOTE-407 study. Bar lengths indicate duration of treatment (dark green) and months of follow-up (light green). aThe patient received subsequent anticancer therapy and had progressive disease (PD) afterwards; the exact dates for these are not known. AE, adverse event; CR, complete response; PD-L1, programmed death ligand 1; PR, partial response; TPS, tumor proportion score.

Median PFS2 was 12.6 (95% CI, 7.9–15.8) months in the pembrolizumab plus chemotherapy group and 8.3 (95% CI, 5.4–10.7) months in the placebo plus chemotherapy group (HR 0.55 [95% CI, 0.29–1.05]; Figure 4). The estimated PFS2 rates were 91% and 68%, respectively, at 6 months and 59% and 27%, respectively, at 12 months.

FIGURE 4. Kaplan–Meier estimate of progression-free survival in the second line (PFS2), defined as the time from randomization to subsequent disease progression (per RECIST version 1.1 assessed by the investigator) after initiation of new anticancer treatment or death from any cause, among Japanese patients enrolled in the KEYNOTE-407 study. chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; mo, months; Pembro, pembrolizumab.

At the time of data cut-off, eight patients (29%) in the placebo plus chemotherapy group crossed over on-study to receive pembrolizumab monotherapy. Among them, seven patients had discontinued pembrolizumab at the time of data cut-off, and one was receiving ongoing treatment.

Safety

Median (range) treatment duration was 5.8 (0.3–23.0) months in the pembrolizumab plus chemotherapy group and 3.4 (0.3–23.4) months in the placebo plus chemotherapy group. All patients in both treatment groups experienced at least one AE (any cause) (Table 4). Grade 3–5 AEs occurred in 19 patients (86%) in the pembrolizumab plus chemotherapy group and 21 patients (75%) in the placebo plus chemotherapy group. The most common grade 3–5 AEs in either treatment group were neutropenia (9 [41%] vs. 6 [21%]), anemia (8 [36%] vs. 6 [21%]), and decreased neutrophil count (4 [18%] vs. 7 [25%]). All patients experienced one or more treatment-related AEs; grade 3–5 treatment-related AEs occurred in 18 (82%) and 20 patients (71%), respectively. There were three deaths due to AEs, two in the pembrolizumab plus chemotherapy group (pneumonia and pneumonitis) and one in the placebo plus chemotherapy group (pulmonary hemorrhage); among them, pneumonitis and pulmonary hemorrhage were considered treatment related by the investigators.

TABLE 4 Summary of all-cause adverse events (AEs) in Japanese patients enrolled in the KEYNOTE-407 study

AE, n (%)	Pembrolizumab + Chemotherapy (n = 22)		Placebo + Chemotherapy (n = 28)
Any AE	22 (100)		28 (100)
Grade 3–5	19 (86)		21 (75)
Treatment related	22 (100)		28 (100)
Leading to any treatment discontinuation	10 (45)		5 (18)
Discontinuation of pembrolizumab or placebo	9 (41)		3 (11)
Discontinuation of carboplatin	7 (32)		3 (11)
Discontinuation of paclitaxel or nab-paclitaxel	8 (36)		5 (18)
Leading to death	2 (9)		1 (4)
Treatment related	1 (5)		1 (4)
AEs occurring in ≥20% of patients in either treatment group, n (%)	Any Grade	Grade 3–5	Any Grade	Grade 3–5
Anemia	19 (86)	8 (36)	18 (64)	6 (21)
Alopecia	17 (77)	0	17 (61)	0
Neutropenia	14 (64)	9 (41)	10 (36)	6 (21)
Constipation	13 (59)	1 (5)	16 (57)	0
White blood cell count decreased	12 (55)	4 (18)	13 (46)	6 (21)
Decreased appetite	11 (50)	1 (5)	18 (64)	1 (4)
Malaise	9 (41)	0	9 (32)	0
Nausea	9 (41)	0	12 (43)	0
Peripheral sensory neuropathy	9 (41)	0	13 (46)	0
Platelet count decreased	9 (41)	1 (5)	4 (14)	0
Diarrhea	8 (36)	2 (9)	6 (21)	1 (4)
Insomnia	8 (36)	0	4 (14)	0
Arthralgia	7 (32)	0	9 (32)	0
Thrombocytopenia	7 (32)	0	4 (14)	2 (7)
Leukopenia	6 (27)	5 (23)	2 (7)	1 (4)
Decreased neutrophil count	6 (27)	4 (18)	9 (32)	7 (25)
Stomatitis	6 (27)	0	4 (14)	0
Pneumonitis	5 (23)	3 (14)	2 (7)	0
Rash	5 (23)	0	5 (18)	0
Upper respiratory tract infection	5 (23)	0	0	0
Pyrexia	4 (18)	0	7 (25)	0
Fatigue	1 (5)	0	6 (21)	0
AE, adverse event.

Immune-mediated AEs and infusion reactions, irrespective of attribution to treatment by the investigator, occurred in 13 patients (59%) in the pembrolizumab plus chemotherapy group and four patients (14%) in the placebo plus chemotherapy group (Table 5). These were of grade 3–5 severity in six (27%) and two patients (7%), respectively. There was one grade 5 immune-mediated AE of pneumonitis in the pembrolizumab plus chemotherapy group.

TABLE 5 Immune-mediated adverse events (AEs) and infusion reactions in Japanese patients enrolled in the KEYNOTE-407 study

	Pembrolizumab + chemotherapy (n = 22)		Placebo + chemotherapy (n = 28)
AE, n (%)	Any grade	Grade 3–5	Any grade	Grade 3–5
Any AEa	13 (59)	6 (27)	4 (14)	2 (7)
Pneumonitis	7 (32)	3 (14)	3 (11)	1 (4)
Infusion reactions	3 (14)	0	0	0
Colitis	2 (9)	1 (5)	1 (4)	1 (4)
Hypophysitis	2 (9)	1 (5)	0	0
Hypothyroidism	2 (9)	0	0	0
Adrenal insufficiency	1 (5)	0	0	0
Hepatitis	1 (5)	1 (5)	0	0
Hyperthyroidism	1 (5)	0	0	0
Severe skin reactions	1 (5)	0	0	0

^aImmune-mediated events were based on a list of terms prespecified prior to the analysis and were included regardless of attribution to study treatment or immune relatedness as determined by the investigator.

DISCUSSION

In this subgroup analysis of the KEYNOTE-407 study, treatment with pembrolizumab in combination with carboplatin and paclitaxel/nab-paclitaxel was associated with prolonged survival outcomes and improved tumor response compared with placebo plus chemotherapy in Japanese patients with previously untreated metastatic squamous NSCLC. Additionally, pembrolizumab plus chemotherapy had manageable toxicity, and no new safety signals were identified.

The median OS was longer in the pembrolizumab plus chemotherapy group compared with the placebo plus chemotherapy group, and the upper limit for the 95% CI was not reached in the pembrolizumab plus chemotherapy group at the time of data cut-off (vs. 19.5 months in the placebo plus chemotherapy group). Whereas longer follow-up will provide more information, the median and HR values suggest long-term benefit of pembrolizumab plus chemotherapy versus placebo plus chemotherapy. Additionally, median PFS2, an investigator-assessed exploratory objective, was longer in the pembrolizumab plus chemotherapy group compared with placebo plus chemotherapy, suggesting that the treatment benefits with pembrolizumab plus chemotherapy might continue into the second line of therapy, as also observed in the KEYNOTE-407 global population.⁵ Importantly, these benefits were observed despite 57% of patients in the placebo plus chemotherapy group having received subsequent anti-PD-(L)1 therapy, which could have attenuated the differences in OS outcomes between the two treatment groups. Overall, trends in outcomes were consistent between the KEYNOTE-407 global population and Japanese patients in this study.^3,5

Pembrolizumab plus chemotherapy had manageable toxicity, as seen in the global KEYNOTE-407 population,⁵ and no new safety signals were identified in Japanese patients. The immune-mediated AE of pneumonitis (based on a prespecified list of terms, regardless of attribution to study treatment or immune-relatedness) occurred more frequently in patients who received pembrolizumab plus chemotherapy (32%) than in patients who received placebo plus chemotherapy (11%). The incidence of this event was higher than in the KEYNOTE-407 global population (8% in the pembrolizumab plus chemotherapy group, 2% in placebo plus chemotherapy group).⁵ Whether this is attributable to an actual increase in reported incidence of this AE, differences in toxicity management, or other reasons, is not known. There are some reports suggesting that squamous tumor histology could be a risk factor for immune checkpoint inhibitor-related pneumonitis development¹⁰ and that pre-existing interstitial lung disease or interstitial lung abnormalities on baseline chest CT imaging are associated with a higher incidence of anti-PD-1 treatment-related pneumonitis.^11,12 Therefore, an independent adjudication committee retrospectively evaluated the events of pneumonitis reported in Japanese patients in this study. Following the review, the committee supported the pneumonitis assessment by the investigators with one exception. A finding of idiopathic pulmonary fibrosis on the baseline chest CT was suggested in a patient who later developed grade 5 pneumonitis; however, per protocol, a patient with current pneumonitis was not eligible for enrollment in this study. Thus, careful attention is warranted for appropriate patient selection to exclude patients with current pneumonitis in clinical practice as well as clinical studies of immune checkpoint inhibitors.

The relatively small number of patients in our subset precludes further analysis of outcomes in key patient subgroups, such as evaluation by PD-L1 TPS, age, and choice of taxane chemotherapy, as well as the potential effects on outcomes in patients who crossed over to pembrolizumab monotherapy from the placebo plus chemotherapy group. In the KEYNOTE-407 global study, pembrolizumab plus chemotherapy showed improved outcomes in all PD-L1 TPS groups analyzed, albeit the magnitude of treatment benefit was greater in patients with tumors that expressed PD-L1 than for patients whose tumors did not express PD-L1.⁵ Similarly, in the small subgroup of Japanese patients presented here, patients with PD-L1 TPS ≥1% appeared to be associated with longer-term benefits compared with those with PD-L1 TPS <1%, as indicated in the swimmer plot. However, this could be a chance observation given that several patients in this subgroup discontinued treatment early, as well as the relatively large proportion of patients with PD-L1 TPS <1% (41%) within this small sample size. The favorable OS and PFS results in this Japanese subset, despite a higher proportion of patients with PD-L1 TPS <1% compared with the global study, further supports the evidence that pembrolizumab plus chemotherapy prolongs OS regardless of PD-L1 TPS. Similar benefits in patients with metastatic NSCLC, regardless of PD-L1 TPS, have been observed across other studies, both in global populations and Asian subgroups.^5,13,14 Given the similarities in baseline characteristics and observed findings between the Japanese and global populations from the KEYNOTE-407 study, we anticipate outcomes comparable to the global population with pembrolizumab plus chemotherapy versus placebo plus chemotherapy for most subgroups in the Japanese population.

In conclusion, an analysis of efficacy and safety outcomes in a subset of Japanese patients from the KEYNOTE-407 study indicated improved survival and durable clinical benefit in patients treated with pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel compared with placebo plus carboplatin and paclitaxel/nab-paclitaxel, with a manageable safety profile.

These data support the Japanese Lung Cancer Society and the Pan-Asian adapted clinical practice guidelines,^2,15 which include recommendations for pembrolizumab plus platinum-based chemotherapy as first-line treatment in Japanese patients with advanced squamous NSCLC.

ACKNOWLEDGMENTS

We thank the patients and their families and caregivers for participating in the studies, along with all investigators and site personnel. We thank Masaru Watanabe, PhD, of MSD K.K. (Tokyo, Japan) for additional study support. Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Medical writing assistance was provided by Kathleen Estes, PhD, of ICON plc (Blue Bell, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. A portion of the results from this study were presented at the 60th Annual Meeting of the Japan Lung Cancer Society, December 6–8, 2019, Osaka, Japan.

FUNDING INFORMATION

Funding for this research was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

CONFLICT OF INTEREST STATEMENT

Shunichi Sugawara: lecture fees from MSD. Kentaro Tanaka: lecture fees and honoraria from MSD, AstraZeneca, Ono Pharmaceutical Co. Ltd, Takeda Pharmaceutical Co. Ltd, Chugai Pharmaceutical Co. Ltd, Bristol Myers Squibb, Eli Lilly Japan, and Merck Biopharma; research funds from Chugai Pharmaceutical Co. Ltd and Boehringer Ingelheim. Nobuyuki Yamamoto: Lecture fees, honoraria or other fees from MSD, AstraZeneca, Ono Pharmaceutical Co. Ltd, Takeda Pharmaceutical Co. Ltd, Chugai Pharmaceutical Co. Ltd, Eli Lilly Japan, and Merck Biopharma; research funds from Chugai Pharmaceutical Co. Ltd, Daiichisankyo, Novartis, Janssen, Eisai, Sanofi, MSD, AstraZeneca, Boehringer Ingelheim, and Eli Lilly Japan. Makoto Nishio: honoraria for lectures and consulting from Ono Pharmaceutical, Bristol Myers Squibb, Pfizer, Chugai Pharmaceutical, Eli Lilly, AstraZeneca, and Takeda. Kyoichi Okishio: lecture fees from Takeda, Chugai, AstraZeneca, and Bristol-Myers Squibb, and pamphlet supervision fees from Sawai Pharmaceuticals. Tomonori Hirashima: research funds from Ono Pharmaceutical, Eli Lilly Japan, AstraZeneca, Taiho Pharmaceutical, Chugai Pharmaceutical, Merck Serono, and MSD. Hiroshi Tanaka: lecture fees, honoraria, or other fees from AstraZeneca, Eli Lilly, Chugai Pharmaceutical, and Ono Pharmaceutical. Tatsuro Fukuhara: research funds from MSD. Takayasu Kurata: honoraria from MSD, Ono, Bristol Myers Squibb, AstraZeneca, Chugai, Nippon Kayaku, Eli Lilly, and Pfizer; research funds from MSD, AstraZeneca, Bristol Myers Squibb, and Takeda. Nobuyuki Katakami: research funds from AstraZeneca, Chugai Pharmaceutical, Delta-Fly Pharmaceutical, MSD, Ono Pharmaceutical, Abbvie, and Boehringer Ingelheim. Morihito Okada: honoraria, lecture fees, or other fees from Johnson and Johnson, AstraZeneca, Ono, Chugai, CSL Behring, and Bristol Myers Squibb; research funds from Eisai, Bristol Myers Squibb, Sanofi, Taiho, and Chugai. Hidehito Horinouchi: lecture fees, honoraria, or other fees from Eli Lilly, AstraZeneca, Kyowa Kirin, MSD, Ono Pharmaceutical, Chugai, Roche, and Bristol Myers Squibb; research funds from Abbvie, MSD, BMS, Ono, Merck Biopharma, Daiichi-Sankyo, Janssen, Genomic Health, Chugai, Roche, and Novartis. Hibiki Udagawa: research funds from Takeda Pharmaceutical Co. Ltd and Boehringer Ingelheim. Kazuo Kasahara: lecture fees, honoraria, or other fees from Eli Lilly, AstraZeneca, Chugai Pharmaceutical Co. Ltd, Ono Pharmaceutical Co. Ltd, Bristol Myers Squibb, and MSD; research fees from MSD, AstraZeneca, and Bristol Myers Squibb. Miyako Satouchi: lecture fees, honoraria, or other fees from AstraZeneca, Chugai, Eli Lilly, Taiho, MSD, Pfizer, Novartis, Bristol Myers Squibb, Ono, Takeda, and Merck; research fees from MSD, IQVIA, Janssen, Chugai, Amgen, Taiho, Ono, Pfizer, Abbvie, and Daiichi-Sankyo. Hideo Saka: lecture fees, honoraria, or other fees from Taiho, AstraZeneca, Ono, Boehringer Ingelheim, Fuji film, Eli Lilly, Chugai, and Kaneka. Takaaki Tokito: grants or contracts from MSD and Janssen; honoraria for lectures from AstraZeneca, Ono Pharmaceutical, MSD oncology, Chugai Pharma, Bristol Myers Squibb, Nippon Kayaku, and Boehringer Ingelheim. Yukio Hosomi: Lecture fees, honoraria, or other fees from AstraZeneca, Chugai, Eli Lilly, Taiho, MSD, Pfizer, Novartis, Bristol Myers Squibb, Ono, Takeda, and Merck. Keisuke Aoe: lecture fees, honoraria, or other fees from Ono and BMS; research fees from AstraZeneca, Ono, Kissei, Eli Lilly, Novartis, BMS, MSD, and Pfizer. Kazuma Kishi: research fees from MSD. Kadoaki Ohashi: research fees from Chugai and Eli Lilly. Noriaki Adachi: Employee of MSD K.K. (Tokyo, Japan) and stockholder in Merck & Co., Inc. (Rahway, NJ, USA). Kazuo Noguchi: employee of MSD K.K. and stockholder in Merck & Co., Inc. Paul Schwarzenberger: former employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. Terufumi Kato: funding for conduct of study from MSD; grants to institution from Abbvie, Amgen, AstraZeneca, Blueprint, Chugai, Eli Lilly, Haihe, Merck Biopharma, MSD, Novartis, Pfizer, Regeneron, and Takeda; honoraria as a speaker for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Merck Biopharma, MSD, Novartis, Ono, Pfizer, and Roche; and honoraria for IDMC or advisory board meeting from Abbvie, Amgen, AstraZeneca, Beigene, Chugai, Daiichi-Sankyo, Eli Lilly, Glaxo, Merck Biopharma, MSD, Nippon Kayaku, Novartis, Ono, Pfizer, Taiho, and Takeda. The other authors have no conflict of interest. [Corrections made on 19 May 2023, after first online publication: Takaaki Tokito’s disclosures were added in this version.]

DATA AVAILABILITY STATEMENT

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD) is committed to providing qualified scientific researchers access to anonymized data and clinical study reports from the company's clinical trials for the purpose of conducting legitimate scientific research. MSD is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The MSD data sharing website (available at: http://engagezone.msd.com/ds_documentation.php) outlines the process and requirements for submitting a data request. Applications will be promptly assessed for completeness and policy compliance. Feasible requests will be reviewed by a committee of MSD subject matter experts to assess the scientific validity of the request and the qualifications of the requestors. In line with data privacy legislation, submitters of approved requests must enter into a standard data-sharing agreement with MSD before data access is granted. Data will be made available for request after product approval in the United States and EU or after product development is discontinued. There are circumstances that may prevent MSD from sharing requested data, including country- or region-specific regulations. If the request is declined, it will be communicated to the investigator. Access to genetic or exploratory biomarker data requires a detailed, hypothesis-driven statistical analysis plan that is collaboratively developed by the requestor and MSD subject matter experts; after approval of the statistical analysis plan and execution of a data-sharing agreement, MSD will either perform the proposed analyses and share the results with the requestor or will construct biomarker covariates and add them to a file with clinical data that is uploaded to an analysis portal so that the requestor can perform the proposed analyses.

ETHICAL APPROVAL

The study was conducted in compliance with the ethical principles originating from the Declaration of Helsinki and with the International Council on Harmonization Good Clinical Practice guidelines and all applicable local and national regulations.

Approval of the research protocol by an institutional review board: The authors declare that the research protocol was approved by an Institutional Review Board.

Informed consent: All patients provided written informed consent before participating in the study.

Registry and registration no. of the study/trial: This study is registered on clinicaltrials.gov (NCT02775435).

Animal studies: N/A.