KEYNOTE‐A17: First‐Line Pembrolizumab Plus Cisplatin–Pemetrexed in Japanese Participants With Advanced Pleural Mesothelioma

ABSTRACT

Pleural mesothelioma (PM) is an inflammatory cancer linked with asbestos exposure and has a poor prognosis. We report results of the phase 1b KEYNOTE‐A17 study (NCT04153565) of first‐line pembrolizumab plus chemotherapy in Japanese participants with advanced PM. Participants aged ≥ 20 years with previously untreated, histologically confirmed advanced or unresectable PM received pembrolizumab 200 mg every 3 weeks (Q3W) for ≤ 35 cycles with cisplatin 75 mg/m² and pemetrexed 500 mg/m² Q3W for 4–6 cycles. Primary endpoints were the rate of dose‐limiting toxicities (DLTs), adverse events (AEs), and treatment discontinuations due to AEs. DLTs were assessed during cycle 1 in 18 participants, and having ≤ 8 participants with DLTs was considered tolerable. AEs were graded per NCI CTCAE 5.0. Tumor response was evaluated per modified RECIST for PM by the investigator. Among 19 participants enrolled, the median study follow‐up was 30.8 (range, 27.8–33.3) months (data cutoff September 21, 2022). Of 18 participants evaluated for DLTs, 2 (11%) experienced 4 DLTs (hypoalbuminemia, malaise, pyrexia in 1 participant; uveitis in 1 participant). 18/19 participants (95%) experienced treatment‐related AEs; 14 (74%) had grade 3–4 events (no grade 5). Treatment‐related AEs led to discontinuation of any drug in 5 participants (26%). The objective response rate was 74% (partial response, n = 14), and the median (range) duration of response was 16.8 (3.0–26.3+) months. First‐line pembrolizumab plus chemotherapy was tolerable based on the low incidence of DLTs and showed acceptable safety and preliminary antitumor activity in Japanese participants with advanced PM.

Trial Registration: NCT04153565

In the phase 1b KEYNOTE‐A17 study of first‐line pembrolizumab plus chemotherapy in Japanese participants with advanced pleural mesothelioma (PM), 2 of 18 participants (11%) evaluated experienced dose‐limiting toxicities. The objective response rate among all 19 participants in the study was 74%, with 14 participants achieving a partial response and a median (range) duration of response of 16.8 (3.0–26.3+) months. Based on these results, first‐line pembrolizumab plus chemotherapy demonstrated acceptable safety and preliminary antitumor activity in Japanese participants with advanced PM.

Abbreviations

AE

adverse event

CPS

combined positive score

CTLA4

cytotoxic T‐lymphocyte antigen 4

DLT

dose‐limiting toxicity

ECOG

Eastern Cooperative Oncology Group

NSCLC

non–small‐cell lung cancer

ORR

objective response rate

PD

progressive disease/disease progression

PD‐1

programmed cell death protein 1

PD‐L1

programmed cell death ligand 1

PM

pleural mesothelioma

RECIST

Response Evaluation Criteria in Solid Tumors

1. Introduction

Pleural mesothelioma (PM) is an aggressive inflammatory cancer linked primarily with exposure to asbestos, which causes pathologic transformations in the mesothelium [1, 2]. PM is a somewhat rare cancer, and diagnosis can be challenging because of difficulties distinguishing it from other tumor types and histologic variability [3]. Because of the long latency period between asbestos exposure and diagnosis (generally, 20–50 years), the incidence of PM is expected to peak over the next couple of decades in developed countries [4, 5]. Prognosis is poor for all stages of the disease, with an estimated 5‐year survival of 3%–6% based on the US SEER National Cancer Database (1973–2011) [2, 4]. Outcomes are similar for patients in Japan, with one study estimating a 3‐year survival rate of 6% among 4120 patients with mesothelioma, 70% of whom had pleural tumors [6]. Available treatment options include surgery, radiation, and/or chemotherapy, but many patients are diagnosed at advanced stages when surgery is not a viable option [2, 7]. Pemetrexed plus cisplatin is a standard first‐line treatment for unresectable PM and provides a modest overall survival benefit, demonstrating a median overall survival of 12 months versus 9 months with cisplatin alone [8]. The combination of nivolumab, an anti–programmed cell death protein 1 (PD‐1) antibody, plus ipilimumab, an anti–cytotoxic T‐lymphocyte antigen 4 (CTLA4) antibody, is now also a standard first‐line treatment based on results from the CheckMate 743 study, which demonstrated improved median overall survival (18 months) with this combination compared with chemotherapy alone (14 months) in patients with previously untreated unresectable PM [9]. Despite this additional treatment option, the overall poor survival outcomes in patients with PM highlight the urgent need for more effective treatments.

Pembrolizumab, an anti–PD‐1 monoclonal antibody, has shown antitumor activity and manageable safety in patients with previously treated PM [10, 11]. In the multicohort phase 1b KEYNOTE‐028 study, pembrolizumab demonstrated an objective response rate of 20% in participants with PM with tumor programmed cell death ligand 1 (PD‐L1) expression of at least 1% who had prior treatment failure or were ineligible for standard therapy [10]. In the multicohort phase 2 KEYNOTE‐158 study, the objective response rate (ORR) with pembrolizumab was 8% among participants with previously treated PM, and responses were observed regardless of PD‐L1 status [11]. Combining pembrolizumab with pemetrexed and platinum‐based chemotherapy could further improve outcomes in patients with PM regardless of tumor PD‐L1 expression. The benefit of combining pembrolizumab with pemetrexed and platinum‐based chemotherapy has been demonstrated in participants with metastatic nonsquamous non–small‐cell lung cancer (NSCLC) in the phase 3 KEYNOTE‐189 study, where this combination treatment showed significant clinical benefit over chemotherapy alone across all subgroups of PD‐L1 tumor proportion scores [12]. Pembrolizumab plus pemetrexed and platinum‐based chemotherapy has also shown benefit versus chemotherapy alone as first‐line therapy in participants with advanced PM in the ongoing phase 3 portion of the KEYNOTE‐483 study (Canadian Clinical Trials Group IND 227), conducted in Canada, Italy, and France [13].

Importantly, race has been shown to be an independent prognostic factor in patients with PM, with Asian patients among those with worse survival outcomes [14]. We conducted the phase 1b open‐label KEYNOTE‐A17 (NCT04153565) study to evaluate the safety and antitumor activity of pembrolizumab plus cisplatin and pemetrexed as first‐line therapy in Japanese participants with previously untreated advanced PM.

2. Material and Methods

2.1. Participants

Eligible participants were at least 20 years of age and had a histologically confirmed diagnosis of advanced or unresectable PM, at least one measurable lesion (≥ 10 mm malignant lesion or ≥ 15 mm malignant lymph node in the short axis) as assessed per modified Response Evaluation Criteria in Solid Tumors (RECIST) for PM by investigator review [15], an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. Participants were excluded if they had received prior anti–PD‐(L)1/2 therapy or an agent directed to another stimulatory or co‐inhibitory T‐cell receptor, systemic therapy for PM, or radiation therapy to the lung greater than 30 Gy within 6 months of the first trial dose; had completed palliative radiation therapy within 7 days of the first dose, had major surgery within 3 months prior to the first dose, or received a live vaccine within 30 days of the first dose; or had known active central nervous system metastases and/or carcinogenic meningitis, active autoimmune disease requiring systemic therapy within the past 2 years, or a history of pneumonitis/interstitial lung disease that required steroid therapy or current pneumonitis/interstitial lung disease (the definition of pneumonitis included radiation pneumonitis). Tumor sample submission for PD‐L1 evaluation was optional.

All participants provided written informed consent. The study was conducted in accordance with the principles of Good Clinical Practice and was approved by an institutional review board/ethics committee at the National Cancer Centre Hospital, JOHAS Okayama Rosai Hospital, Hyogo College of Medicine Hospital, and Kanagawa Cancer Centre.

2.2. Study Design and Treatments

In this multicenter, open‐label, single‐arm phase 1b study, participants received pembrolizumab 200 mg every 3 weeks (Q3W) in combination with cisplatin 75 mg/m² Q3W and pemetrexed 500 mg/m² Q3W for 4–6 cycles. Participants continued to receive pembrolizumab for up to a total of 35 cycles or until disease progression (PD) per modified RECIST for PM by investigator review, unacceptable adverse events (AEs), recurrent grade 2 or any grade 3 or 4 pneumonitis, or the investigator's decision. Participants received appropriate vitamin B12 and folic acid supplementation, prophylactic dexamethasone for pemetrexed treatment, and appropriate hydration for cisplatin treatment based on the local institutional practice. The order of administration was pembrolizumab first, then pemetrexed, followed by a 30‐min interval once the infusion was completed, after which cisplatin was administered.

2.3. Assessments

Dose‐limiting toxicities (DLTs) were evaluated during the first 3 weeks after initiation of study treatment (DLT evaluation period) and were defined as any of the following toxicities that were deemed by the investigator to be treatment‐related: grade 4 hematologic toxicities except neutropenia and febrile neutropenia (any period); grade 4 neutropenia lasting greater than 7 days despite supportive treatment; grade 4 febrile neutropenia (any period), only if the event was considered clinically significant for the participant; any grade 4 nonhematologic toxicity; any grade 3 nonhematologic toxicity lasting greater than 72 h despite appropriate supportive care; any grade 4 laboratory test value abnormality; any grade 3 laboratory test value abnormality lasting greater than 7 days; toxicity related to study procedures that resulted in greater than 2‐week delay in the start of cycle 2; any grade 5 toxicity.

Safety was assessed throughout the study and for 30 days after cessation of study treatment (90 days for serious AEs). AEs, including DLTs, were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.

Radiographic imaging was performed at baseline (within 28 days before first dose), at 6 weeks after the first dose, and every 6 weeks thereafter until week 24. Imaging was then performed every 9 weeks until the end of the first year and every 12 weeks thereafter. After participants completed study treatment or discontinued for reasons other than radiologic PD per modified RECIST for PM per investigator review, radiographic monitoring continued every 12 weeks until radiologic PD, the start of new anticancer therapy, pregnancy, death, withdrawal of consent, or the end of the study.

If available at baseline, tumor tissue samples (archival or newly obtained) were assessed for PD‐L1 expression using PD‐L1 IHC 22C3 pharmDx (Agilent Technologies, Carpinteria, CA, USA). PD‐L1 expression was measured using the combined positive score (CPS), defined as the number of PD‐L1–staining cells (tumor cells, lymphocytes, and macrophages) divided by the total number of viable tumor cells, multiplied by 100.

2.4. Outcomes

The primary endpoints were DLT rate (proportion of participants with DLTs observed during DLT evaluation period), incidence of AEs, and discontinuation of study treatment due to AEs. Secondary endpoints were objective response rate (proportion of participants with a confirmed complete response or partial response), disease control rate (proportion of participants with confirmed complete response or partial response or stable disease), and duration of response (time from first documented evidence of complete response or partial response to earliest date of PD or death due to any cause). Exploratory endpoints included progression‐free survival (time from first dose of study treatment to first documented PD or death from any cause), overall survival (time from first dose of study treatment to death from any cause), and objective response by baseline tumor PD‐L1 expression. Tumor response was evaluated per modified RECIST in PM by investigator review.

2.5. Statistical Analysis

The DLT‐evaluable population included all participants who received at least 1 dose of study drug, received at least 90% of planned study drug and completed all safety evaluations during the DLT evaluation period. Safety and efficacy were analyzed in the all‐participants‐as‐treated population, which included all participants who received at least 1 dose of study drug. Planned enrollment for the study was up to 18 evaluable participants to assess the tolerability of pembrolizumab plus chemotherapy. The study regimen was deemed tolerable if eight or fewer of 18 participants developed a DLT, using a modified toxicity probability interval (mTPI) design; however, the target DLT rate was 30% [16]. Per dose‐finding rules of the mTPI design, the decisions "escalate to the next higher dose" or "stay at the current dose" were considered as “tolerated” and supportive for further investigation. AEs were summarized by counts and frequencies. For objective response rate and disease control rate, the point estimate of the 95% CI was evaluated using the Clopper–Pearson interval. The Kaplan–Meier method was used for analysis of duration of response, progression‐free survival, and overall survival. Participants who had not died were censored from the overall survival analysis on the date of the last study assessment or contact.

2.6. Role of the Funding Source

The KEYNOTE‐A17 study was designed by representatives of the study sponsor. Data were collected by the investigators at study sites and were analyzed and interpreted by the author group. All authors had full access to the data. The authors received medical writing assistance in preparing the manuscript, which was supported by the sponsor. All authors were responsible for the decision to submit the manuscript for publication.

3. Results

3.1. Participants

A total of 22 participants were screened, of which 3 were screen failures (Figure 1). Nineteen Japanese participants with advanced or unresectable PM were enrolled between December 12, 2019, and May 28, 2020. Median time from first dose to data cutoff date (September 21, 2022) was 30.8 (range, 27.8–33.3) months. As of data cutoff, 4 participants (21%) had completed treatment and 15 participants (79%) had discontinued treatment due to radiographic PD (n = 7), AEs (n = 4), clinical progression (n = 2), or withdrawal of consent (n = 2). The median number of treatment cycles was 11.0 (range, 1.0–35.0); 11 participants (58%) had at least 6 months, 6 participants (32%) had at least 12 months, and 5 participants (26%) had at least 18 months of treatment exposure, respectively. Most participants had epithelioid tumors (15/19 [79%]) and prior exposure to asbestos (14/19 [74%]; Table 1).

FIGURE 1.

CONSORT flow diagram for the KEYNOTE‐A17 study. ^aOne participant withdrew consent during cycle 1 without a DLT and, per protocol, was excluded from the DLT‐evaluable population.

TABLE 1.

Participant demographics and baseline disease characteristics.

Characteristic	N = 19
Age, median (range), years	70 (54–78)
Male	15 (79)
ECOG PS
0	2 (11)
1	17 (89)
Environmental exposure to asbestos	14 (74)
Histology
Epithelioid	15 (79)
Sarcomatoid	2 (11)
Biphasic	2 (11)
Previous treatment
Systemic therapy a	6 (32)
Radiation	0
Surgery b	4 (21)
PD‐L1 status
CPS ≥ 1	5 (26)
CPS < 1	3 (16)
CPS unknown	11 (58)

Note: Data in table are n (%) unless otherwise noted.

Abbreviations: CPS, combined positive score; ECOG PS, Eastern Cooperative Oncology Group performance status; PD‐L1, programmed cell death ligand 1.

^a Participants who received (neo)adjuvant therapy, with the last dose completed ≥ 6 months before enrollment.

^b Participants who received major surgery ≥ 3 months before the first dose.

3.2. Safety

One participant withdrew consent during cycle 1 without DLT and, per protocol, was excluded from the DLT‐evaluable population. Among the 18 participants included in the DLT‐evaluable population, 2 participants (11%) experienced a total of four DLTs. One participant experienced three DLTs: grade 3 hypoalbuminemia, which did not result in any dose modifications and had not resolved as of the last follow‐up before data cutoff, and grade 3 malaise and grade 2 pyrexia, both of which resulted in discontinuation of cisplatin and interruption of pembrolizumab and pemetrexed and had resolved as of the last follow‐up before data cutoff. The second participant experienced one DLT of grade 3 uveitis that resulted in discontinuation of all study drugs and had not resolved as of the last follow‐up before data cutoff.

All 19 participants enrolled in the study received at least 1 dose of study treatment and were included in safety analyses. Most participants (18/19 [95%]) experienced at least one treatment‐related AE, with the most common events being nausea (n = 16), constipation (n = 12), and anemia (n = 11; Table 2). Grade 3–4 treatment‐related AEs occurred in 14 participants (74%), and there were no grade 5 treatment‐related AEs. Five participants (26%) experienced at least one treatment‐related AE that led to discontinuation of any study drug: grade 3 events of pneumonitis (n = 2), febrile neutropenia (n = 1), malaise (n = 1), and uveitis (n = 1; all drugs discontinued); and grade 2 events of hypersensitivity (n = 1) and pyrexia (n = 1). One participant died from bacterial pneumonia that was not considered by the investigator to be related to study treatment. Immune‐mediated AEs and infusion reactions, irrespective of attribution to treatment by the investigator, occurred in 7 participants (37%) (Table 2); grade 3–5 events occurred in 3 participants (16%), all of which were grade 3 in severity (pneumonitis [n = 2] and uveitis [n = 1]).

TABLE 2.

Summary of AEs in participants who received at least 1 dose of study treatment.

	N = 19
Any treatment‐related AE a	18 (95)
Grade 3	12 (63)
Grade 4	2 (11)
Grade 5	0
Led to treatment discontinuation
Any drug	5 (26)
All drugs	1 (5)
Treatment‐related AEs with incidence ≥ 10%	Any grade	Grade 3–4
Nausea	16 (84)	0
Constipation	12 (63)	0
Anemia	11 (58)	8 (42)
Malaise	9 (47)	1 (5)
Decreased white blood cells	7 (37)	2 (11)
Diarrhea	7 (37)	0
Dysgeusia	6 (32)	0
Neutropenia	6 (32)	3 (16)
Decreased appetite	5 (26)	1 (5)
Hiccups	5 (26)	1 (5)
Decreased neutrophils	4 (21)	4 (21)
Pneumonitis	5 (26)	2 (11)
Rash	4 (21)	0
Arthritis	2 (11)	0
Hyponatremia	3 (16)	1 (5)
Renal impairment	3 (16)	0
Febrile neutropenia	2 (11)	2 (11)
Hypothyroidism	2 (11)	0
Eczema	2 (11)	0
Pyrexia	2 (11)	0
Stomatitis	2 (11)	0
Vomiting	2 (11)	0
Immune‐mediated AEs and infusion reactions b	7 (37)	3 (16) c
Pneumonitis	5 (26)	2 (11)
Hypothyroidism	2 (11)	0
Infusion reactions	1 (5)	0
Uveitis	1 (5)	1 (5)

Abbreviation: AE, adverse event.

^a AEs determined by the investigator to be related to study treatment.

^b Events were based on a list of terms specified at the time of analysis and were included regardless of attribution to study treatment or immune relatedness by the investigator. Related terms were included.

^c There were no grade 4 or 5 immune‐mediated AEs or infusion reactions.

Among 5 participants who had treatment‐related pneumonitis (Table 2), 3 experienced grade 2 events, and 2 had grade 3 events. Of the 2 participants who experienced grade 3 pneumonitis, both participants discontinued treatment, and at the time of data cutoff, pneumonitis was resolved for one participant.

3.3. Efficacy

Among all 19 participants, the objective response rate was 74% (95% CI, 49%–91%). The objective response rate was similar in participants with epithelioid and non‐epithelioid tumor histology (73% and 75%, respectively) and in participants with PD‐L1 CPS of at least 1 and CPS less than 1 (80% and 100%, respectively), although the number of participants in each subgroup was small (Table 3). The best overall response was a partial response in 14 participants and stable disease in 4 additional participants, resulting in a disease control rate of 95%. The median duration of response, as estimated by the Kaplan–Meier method, was 16.8 months (range, 3.0–26.3+ months; with + indicating no PD at the time of last disease assessment).

TABLE 3.

Confirmed objective response per modified RECIST for PM by investigator review.

	Overall (N = 19)	Epithelioid (n = 15)	Non‐epithelioid (n = 4)	PD‐L1 CPS ≥ 1 (n = 5)	PD‐L1 CPS < 1 (n = 3)
Objective response rate, % (95% CI)	74 (49–91)	73 (45–92)	75 (19–99)	80 (28–99)	100 (29–100)
Best overall response, n (%)
Complete response	0	0	0	0	0
Partial response	14 (74)	11 (73)	3 (75)	4 (80)	3 (100)
Stable disease	4 (21)	3 (20)	1 (25)	1 (20)	0
Progressive disease	0	0	0	0	0
No assessment a	1 (5)	1 (7)	0	0	0
Disease control rate, n (%)	18 (95)	14 (93)	4 (100)	5 (100)	3 (100)

Abbreviations: CPS, combined positive score; PD‐L1, programmed cell death ligand 1; PM, pleural mesothelioma; RECIST, Response Evaluation Criteria in Solid Tumors.

^a No assessment: No postbaseline assessment available for response evaluation.

Among 18 participants with at least one postbaseline tumor assessment, most had a best percentage change from baseline in target lesion size that was a greater than a 30% reduction from baseline (Figure 2A). Most participants with available postbaseline data experienced sustained reductions in tumor size (Figure 2B). Among the 14 participants with a confirmed partial response, 12 participants experienced a response within the first 2–3 months of treatment, and two had an ongoing response as of the last follow‐up before the data cutoff (Figure 3).

FIGURE 2.

Changes from baseline in size of target lesions per modified RECIST for PM by investigator review. (A) Best change from baseline in tumor size. (B) Percentage change from baseline in tumor size over time. CPS, combined positive score; PD‐L1, programmed cell death ligand 1; PM, pleural mesothelioma; RECIST, Response Evaluation Criteria in Solid Tumors. [Correction added on 9 June 2025, after first online publication. “weeks” has been amended to “months” in the horizontal axis of Figure 2.]

FIGURE 3.

Time to response and time to progression per modified RECIST for PM by investigator review. Bar lengths indicate time to last response assessment. ^aAll other participants represented in the figure had epithelioid tumors. CPS, combined positive score; PD‐L1, programmed cell death ligand 1; PM, pleural mesothelioma; RECIST, Response Evaluation Criteria in Solid Tumors.

As of the data cutoff date, 13 of 19 participants (68%) had died or experienced PD. Median progression‐free survival was 13.8 months (95% CI, 4.8–27.4 months), and the estimated 12‐month progression‐free survival rate was 64% (Figure 4A). As of the data cutoff, 13 of 19 participants (68%) had died. Median overall survival was 20.9 months (95% CI, 8.3 months–not reached), and the estimated 12‐month overall survival rate was 68% (Figure 4B).

FIGURE 4.

Kaplan–Meier survival estimates. (A) Progression‐free survival per modified RECIST for PM by investigator review. (B) Overall survival. NR, not reached; PM, pleural mesothelioma; RECIST, Response Evaluation Criteria in Solid Tumors.

4. Discussion

In this phase 1b study, pembrolizumab plus cisplatin and pemetrexed demonstrated acceptable safety and tolerability in Japanese participants with previously untreated advanced PM. DLTs occurred in 11% of participants, which was below the prespecified threshold for tolerability, and 26% of participants discontinued treatment due to treatment‐related AEs. There were no grade 5 treatment‐related AEs. The most common treatment‐related AEs were consistent with the safety profile of pembrolizumab plus pemetrexed and platinum‐based chemotherapy observed in Japanese and global study populations of participants with metastatic nonsquamous NSCLC [17, 18]. These included nausea, constipation, and anemia as the most common all‐cause AEs reported. As expected with a treatment regimen that includes pemetrexed and platinum‐based chemotherapy, the most frequently occurring grade 3–4 treatment‐related AEs we observed were anemia, decreased neutrophils, and neutropenia [17, 18]. Notably, the types of treatment‐related AEs observed in our study were similar to treatment‐emergent AEs reported in a phase 1/2 study of cisplatin and pemetrexed in Japanese participants with previously untreated PM [19], suggesting no new safety signals with the addition of pembrolizumab to this treatment regimen.

The incidence of pneumonitis was higher in this study (26% [n = 5/19]) than that previously observed with the combination of pembrolizumab plus pemetrexed‐platinum in the randomized, phase 3 KEYNOTE‐189 Japan study in metastatic nonsquamous NSCLC (8% [n = 2/25] in the pembrolizumab plus chemotherapy group, 13% [n = 2/15] in the placebo plus chemotherapy group) [18]. Certain histologies, such as squamous tumor histology, have been reported to be associated with a higher incidence of immune checkpoint inhibitor‐related pneumonitis when compared with adenocarcinoma [20]. With the small number of participants and single‐arm design of this study, it is unclear whether tumor type may have contributed to the incidence of pneumonitis we observed. However, since the number of patients with advanced PM treated with pembrolizumab plus cisplatin and pemetrexed is limited, selection of appropriate patients and close monitoring for the incidence of pneumonitis are warranted.

The objective response rate of 74% provided preliminary evidence of antitumor activity with pembrolizumab plus chemotherapy in Japanese participants. All responders had a best overall response of partial response, and median duration of response was 17 months, with ongoing response in two participants as of the data cutoff for this analysis. The estimated 12‐month progression‐free survival and overall survival rates were also encouraging, both exceeding 60%. Additionally, most participants experienced a maximum reduction in tumor size of greater than 30% compared to baseline. It is also notable that, although patients with non‐epithelioid histology have historically had less favorable outcomes [4], three of the four participants in our study with sarcomatoid or biphasic histology had objective responses, and the remaining participant had stable disease. Objective responses were also observed irrespective of PD‐L1 CPS, although the number of participants with known PD‐L1 status was small.

Based on historical data, the combination of cisplatin and pemetrexed has demonstrated an objective response rate of 41% in patients with previously untreated PM [8]; therefore, the objective response rate of 74% with pembrolizumab plus cisplatin and pemetrexed that we observed among the 19 participants in our study suggests promising antitumor activity with this regimen in PM. The ongoing phase 2/3 KEYNOTE‐483 study (Canadian Clinical Trials Group IND 227) is evaluating pembrolizumab as first‐line therapy with or without chemotherapy versus chemotherapy alone in participants with advanced PM. In the phase 2 open‐label part of the trial, PFS (primary endpoint) was similar with pembrolizumab with or without chemotherapy versus chemotherapy alone (HR for pembrolizumab plus chemotherapy vs. chemotherapy, 0.55 [95% CI, 0.38–1.06] and for pembrolizumab vs. chemotherapy, 0.69 [95% CI, 0.36–1.33]), although OS was numerically longer with pembrolizumab plus chemotherapy versus chemotherapy alone (HR, 0.36; 95% CI, 0.18–0.72) [21]. In the phase 3 part of the study, OS (primary endpoint) HR was 0.79 (95% CI, 0.64–0.98; p = 0.0324) and PFS HR was 0.80 (95% CI, 0.65–0.99; p = 0.0372) favoring pembrolizumab plus chemotherapy versus chemotherapy alone, with a significantly higher overall response rate in the pembrolizumab plus chemotherapy group (62% vs. 38%; p < 0.0001) [13]. These results, coupled with those presented here in Japanese participants, provide promising evidence of clinical benefit with pembrolizumab plus chemotherapy in previously untreated advanced PM. Given that mortality from PM is expected to rise in Japan in the next few years [22], these results provide important information for the development of new treatment options for Japanese patients with PM.

Our preliminary findings also compare favorably with results from prior studies in PM that include a PD‐(L)1 inhibitor in the treatment regimen [9, 23, 24]. In phase 2 single‐arm studies in participants with previously untreated, unresectable PM, durvalumab or nivolumab plus cisplatin and pemetrexed demonstrated an objective response rate of 56% or 78%, respectively [23, 24]. Additionally, in the phase 3 CheckMate 743 study, nivolumab plus ipilimumab demonstrated an objective response rate of 40% versus 44% with standard cisplatin or carboplatin and pemetrexed chemotherapy in participants with previously untreated, unresectable PM [9].

Limitations of this phase 1b trial include the small study population, which makes it difficult to interpret results among subgroups of participants. Although efficacy results presented here suggest that pembrolizumab plus cisplatin and pemetrexed may provide clinical benefit in patients with previously untreated PM, irrespective of histology or tumor PD‐L1 expression, the study was not powered to assess antitumor activity. Lastly, because tumor samples for evaluation of PD‐L1 status were not required for enrollment in this trial, CPS was unknown for many participants.

In conclusion, pembrolizumab plus cisplatin and pemetrexed demonstrated an acceptable safety profile in Japanese participants with previously untreated advanced or unresectable PM. Our results also provide preliminary evidence suggesting that the combination of pembrolizumab plus standard chemotherapy could offer a promising treatment option for Japanese patients with advanced PM.

Author Contributions

Takashi Kijima: conceptualization, investigation, writing – review and editing. Terufumi Kato: investigation, writing – review and editing. Yasushi Goto: conceptualization, investigation, writing – review and editing. Kozo Kuribayashi: investigation, resources, writing – review and editing. Koji Mikami: investigation, writing – review and editing. Yoshiki Negi: investigation, resources, writing – review and editing. Shuji Murakami: investigation, writing – review and editing. Tatsuya Yoshida: investigation, writing – review and editing. Masae Homma: conceptualization, investigation, writing – review and editing. Akira Wakana: conceptualization, investigation, writing – review and editing. Kazuo Noguchi: conceptualization, investigation, writing – review and editing. Nobukazu Fujimoto: investigation, writing – review and editing.

Ethics Statement

The protocol and its amendments were approved by an institutional review board/ethics committee at the National Cancer Centre Hospital, JOHAS Okayama Rosai Hospital, Hyogo College of Medicine Hospital, and Kanagawa Cancer Centre in accordance with the Declaration of Helsinki. All participants provided written informed consent before participation in the study.

Conflicts of Interest

Takashi Kijima: Support for the current manuscript: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Honoraria for lecture fee: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Advisory board: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Terufumi Kato: Support for the current manuscript: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Honoraria for speaker to self: Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi‐Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Merck KGaA, MSD, Novartis, Ono, Pfizer, Taiho, and Takeda. Grants for commissioned/joint research to institution: AbbVie, Amgen, Arrivent, AstraZeneca, Bayer, BeiGene, BluePrint, Bristol Myers Squibb, Chugai, Daiichi‐Sankyo, Eli Lilly, Gilead, GlaxoSmithKline, Haihe, Janssen, Merck KGaA, MSD, Novartis, Pfizer, Regeneron, and Takeda. Honoraria for IDMC or advisory board meeting to self: AstraZeneca, BeiGene, Chugai, Daiichi‐Sankyo, Janssen, Merck KGaA, MSD, Novartis, Pfizer. Employer (spouse): Eli Lilly. Yasushi Goto: Honoraria to self: Eli Lilly, Chugai, Taiho, Boehringer Ingelheim, Ono, Bristol Myers Squibb, Pfizer, MSD, Novartis, Merck, Thermo Fischer. Grants for commissioned/joint research: AbbVie, Eli Lilly, Pfizer, Bristol Myers Squibb, Ono, Novartis, Kyorin, Daiichi‐Sankyo, Novartis, Prefered Network. Participation on data safety monitoring board or advisory board to self: AstraZeneca, Chugai, Boehringer Ingelheim, Eli Lilly, Taiho, Pfizer, Novartis, Guardant Health Inc., Illumina, Daiichi‐Sankyo, Ono Pharmaceutical, Bristol Myers Squibb, MSD. Leadership or fiduciary role: Cancer Net Japan, JAMT. Editorial Board Member: Cancer Science. Shuji Murakami: Grants or contracts to institution: AstraZeneca, Takeda, Chugai Pharma, Sanofi, MSD, Daiichi‐Sankyo, Ono Pharmaceutical, Janssen Pharma. Honoraria to self: AstraZeneca, Chugai Pharma, Takeda, Eli Lilly, MSD, Pfizer, Novartis, Taiho Pharmaceutical. Tatsuya Yoshida: Grants or contracts from: Novartis, AbbVie, Amgen, Daiichi‐Sankyo, AstraZeneca, MSD, Chugai, Astellas, Medpace, Boehringer Ingelheim, BMS, Ono, and Merck Biopharma. Payment or honoraria: Novartis, Daiichi‐Sankyo, AstraZeneca, MSD, Chugai, BMS, Ono, Takeda, Pfizer, Lilly, and Merck Biopharma. Participation on a Data Safety Monitoring Board or Advisory Board: Novartis, MSD, Amgen, Chugai, Pfizer, and Boehringer Ingelheim. Masae Homma: Employee of MSD K.K., Tokyo, Japan. Akira Wakana: Employee of MSD K.K., Tokyo, Japan, and owns stock in Merck & Co., Inc., Rahway, NJ, USA. Kazuo Noguchi: Employee of MSD K.K., Tokyo, Japan. Nobukazu Fujimoto: Payment or honoraria to self: Ono Pharmaceutical, Bristol Myers Squibb, AstraZeneca, Chugai Pharmaceutical, MSD, Nihon Kayaku, Boehringer Ingelheim. Participation on a Data Safety Monitoring Board or Advisory Board to self: Ono Pharmaceutical, AstraZeneca. The other authors declare no conflicts of interest.

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: https://externaldatasharing‐msd.com/) 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 US 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.