Phase II Efficacy and Safety of Pembrolizumab with Platinum Based Chemotherapy in Non–Small Cell Lung Cancer Patients with Untreated, Asymptomatic Brain Metastasis (PHOEBS)

Article information

J Korean Cancer Assoc. 2026;.crt.2025.1100

Publication date (electronic) : 2026 March 19

doi : https://doi.org/10.4143/crt.2025.1100

, Miran Han ¹, Jinyong Kim ¹, Sehhoon Park ¹, Hyun Ae Jung ¹, Jong-Mu Sun ¹, Se-Hoon Lee ¹, Jin Seok Ahn ¹, Sun Hye Shin ², Kyungjong Lee ², Sang-Won Um ², Myung-Ju Ahn^,¹

¹Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

²Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Correspondence: Myung Ju Ahn, Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: 82-2-3410-3459 E-mail: silkahn@skku.edu

Received 2025 October 10; Accepted 2026 March 18.

Abstract

Purpose

Brain metastases are a serious complication in non–small cell lung cancer (NSCLC). However, data regarding efficacy of immune checkpoint inhibitors and chemotherapy combinations are limited. This phase II study aimed to evaluate the intracranial efficacy and safety of pembrolizumab and chemotherapy in treatment-naïve NSCLC patients with asymptomatic brain metastases.

Materials and Methods

This single-arm, phase II trial was conducted at Samsung Medical Center, Korea. Eligible patients had stage IV NSCLC with asymptomatic, untreated brain metastases and no epidermal growth factor receptor or anaplastic lymphoma kinase alterations. Patients received pembrolizumab with chemotherapy every 3 weeks for 4 cycles, followed by pembrolizumab with or without maintenance chemotherapy up to 35 cycles. The primary endpoint was intracranial objective response rate (icORR). Secondary endpoints included intracranial progression-free survival (icPFS), intracranial duration of response (icDoR), objective response rate, progression-free survival (PFS), overall survival (OS), and safety.

Results

Between February 2021 and June 2024, a total of 13 patients were enrolled. Due to challenges in recruiting patients, enrollment was discontinued after the 13 patients. The icORR was 46.2% (95% confidence interval [CI], 19.2 to 74.9), with six patients achieving partial response. The median icPFS was 9.8 months (95% CI, 5.2 to 21.5), and median icDoR was 9.3 months (95% CI, 4.0 to 20.3). Median PFS and OS were 7.2 months (95% CI, 2.4 to 12.3) and 10.7 months (95% CI, 7.2 to 21.5), respectively. Most treatment-related adverse events were grade 1-2.

Conclusion

Pembrolizumab combined with chemotherapy demonstrated encouraging intracranial activity and manageable safety profile in NSCLC patients with untreated, asymptomatic brain metastases.

Keywords: Non-small-cell lung carcinoma; Brain metastasis; Pembrolizumab; Drug therapy

Introduction

In patients with non–small cell lung cancer (NSCLC), brain metastasis negatively impacts quality of life and prognosis [1,2]. At initial diagnosis, approximately 5%-10% of patients with lung cancer present with brain metastases, and cumulative incidence increases to 20%-40% over the course of the treatment [2,3]. Given the adverse impact of brain metastases on both survival outcomes and quality of life, patients with brain metastases represent a population with a considerable unmet need, underscoring the importance of developing more effective therapeutic options.

The current treatment options for patients with brain metastasis depend on the patient’s neurologic symptom and molecular profiling. For patients with brain metastases, local therapies such as surgical resection, stereotactic radiosurgery, and whole brain radiotherapy (WBRT) are one of the treatment options [4,5]. However, these modalities are associated with substantial treatment-related toxicities such as neurocognitive dysfunction and delay in delivering systemic therapy [6], during which extracranial disease progression may occur. In patients with minimal neurologic symptoms and actionable oncogenic alterations identified through molecular profiling, upfront systemic therapy using blood-brain barrier-penetrating small molecule tyrosine kinase inhibitors may be considered as initial treatment strategy [7,8]. However, in patients without such actionable genomic alterations, the efficacy of first-line treatment approach remains questionable. The introduction of pembrolizumab, a programmed cell death 1 (PD-1) inhibitor, in combination with platinum-based chemotherapy has established a new first-line treatment option for patients with NSCLC lacking epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) alterations [9,10]. Although patients with baseline brain metastases were included in these pivotal trials, dedicated data regarding the efficacy and safety of this regimen specifically in the subset of patients with brain metastases remain limited.

To address this issue, we conducted a single-arm, phase II trial to evaluate the intracranial response, progression-free survival (PFS) and safety outcomes in patients with asymptomatic brain metastases at diagnosis treated with pembrolizumab in combination with platinum-based chemotherapy.

Materials and Methods

1. Study design and participants

This phase II, open-label, single-arm, single-center study was conducted at Samsung Medical Center, Republic of Korea. We enrolled patients with baseline brain metastasis to evaluate safety and efficacy of pembrolizumab in combination with platinum-based chemotherapy. Eligible patients were 18 years or older, had a pathologically confirmed advanced NSCLC and asymptomatic brain metastases at the time of diagnosis. Key eligibility criteria included treatment-naive stage IV NSCLC with the presence of asymptomatic brain metastases with at least one intracranial lesion measuring ≥ 10 mm in diameter, molecular profiling confirming no actionable genomic alterations such as EGFR or ALK mutations, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ functions. Those who had received prior adjuvant or neoadjuvant chemotherapy following surgical resection were considered eligible if such treatment had been completed at least six months before the onset of metastatic disease. Key exclusion criteria comprised prior exposure to immune checkpoint inhibitors (ICIs), including anti–PD-1, anti–programmed cell death ligand 1 (PD-L1), or anti–cytotoxic T-lymphocyte antigen-4 agents; receipt of whole-brain radiotherapy (WBRT); absence of measurable intracranial lesions apart from those previously treated with stereotactic radiosurgery or surgical resection; and administration of radiotherapy within one week prior to study enrollment, unless patients had fully recovered from radiation-related toxicities, were not receiving corticosteroids, and had no clinical or radiographic evidence of radiation pneumonitis. Additional exclusion criteria included active leptomeningeal disease; a history of other malignancies within 3 years prior to study treatment, with the exception of cutaneous squamous cell carcinoma, basal cell carcinoma, early-stage gastric cancer, thyroid carcinoma, or cervical intraepithelial neoplasia; active autoimmune disease requiring systemic immunosuppressive therapy within the past two years; and prior allogeneic tissue or solid organ transplantation. Complete eligibility criteria are outlined in Supplementary Methods.

2. Procedures and assessments

Treatment regimens were selected based on histological subtype following a diagnosis of stage IV NSCLC. Patients with non-squamous NSCLC received intravenous pembrolizumab at a fixed dose of 200 mg in combination with pemetrexed (500 mg/m²) and carboplatin (area under the curve [AUC], 5.0), while patients with squamous cell carcinoma received pembrolizumab (200 mg) combined with paclitaxel (200 mg/m²) and carboplatin (AUC, 6.0). All agents were administered on day 1 of each 21-day cycle for four cycles. After the 4 cycles, for patients with non-squamous histology, maintenance therapy with pemetrexed (500 mg/m²) and pembrolizumab (200 mg) was administered every 3 weeks for up to a total of 35 cycles. For patients with squamous cell histology, pembrolizumab monotherapy (200 mg every 3 weeks) was continued for up to a total of 35 cycles or until disease progression, unacceptable toxicity, or death. Up to two dose reductions of chemotherapy were permitted, as assessed by the Common Terminology Criteria for Adverse Events (CTCAE). Patients requiring a third dose reduction discontinued the respective agent. At the investigator’s discretion, patients could discontinue chemotherapy and continue pembrolizumab monotherapy, or vice versa. Chemotherapy was allowed to be withheld for up to 6 weeks, and pembrolizumab for up to 12 weeks.

Screening assessments included clinical examination, complete blood count with differential, comprehensive metabolic panel, thyroid function test, electrocardiogram, and chest X-ray. Clinical examinations, routine laboratory tests, and chest radiographs were performed following each treatment cycle to monitor treatment-related adverse events (TRAEs). Baseline imaging with chest computed tomography (CT), positron emission tomography (PET)–CT, and brain magnetic resonance imaging (MRI) was performed within 28 days prior to the first dose of study treatment. Follow-up CT and brain MRI were conducted every 6 weeks from the start of treatment, and every 9 weeks after 12 months of therapy. PET-CT was performed at screening and optionally during the study at the discretion of the investigator.

For patients who discontinued study treatment, imaging was performed at the time of treatment discontinuation unless radiologic assessments had been completed within the preceding 4 weeks.

3. Outcomes

The primary endpoint was intracranial objective response (icORR) rate according to Response Evaluation Criteria in Solid Tumors (RECIST) ver. 1.1. Secondary endpoints included PFS and overall survival (OS), intracranial duration of response (icDoR) and intracranial progression-free survival (icPFS), objective response rate (ORR) and safety. All analyses were based on the full analysis set (FAS), defined as all patients who received at least one dose of pembrolizumab. icORR was defined as the proportion of patients whose best intracranial response was either a complete response (CR) or partial response (PR). icDoR was defined as the time from initial documented intracranial response to intracranial disease progression. icPFS was defined as the time from treatment initiation to the progression of intracranial lesions. PFS was defined as the time from initiation of chemotherapy to documentation of either disease progression or death from any cause. OS was defined as the time from chemotherapy initiation to death from any cause. ORR was defined as the proportion of patients whose best response was CR or PR, assessed by RECIST ver. 1.1. Safety profiles were documented by CTCAE ver. 5.0.

4. Statistical analysis

We calculated the sample size based on the primary endpoint, icORR. This study was designed for 90% power to reject the null hypothesis that the icORR in the historical control group treated with cytotoxic chemotherapy alone is 20%. A one-sided alpha level of 0.05 was used, and the expected icORR with the combination of pembrolizumab and cytotoxic chemotherapy was assumed to be 40%. This assumption was based on the result of KEYNOTE-189 and KEYNOTE-407. A sample size of 45 patients was required. Accounting for an anticipated 10% dropout rate, the final target sample size was determined to be 50 patients for the primary analysis.

Categorical variables were presented as counts and percentages and continuous variables with medians and ranges. Response was calculated with 95% confidence interval (CI) by the exact binomial method. The Kaplan-Meier method was used to estimate PFS, duration of response, and OS.

Results

1. Baseline demographics

From February 2021 through June 2024, a total of 15 patients were screened, of whom 13 received treatment and were included in the FAS for the assessment of icORR and other secondary outcomes. Due to challenges in recruiting patients with asymptomatic brain metastases and intracranial lesions measuring ≥ 10 mm in diameter, enrollment was discontinued after the inclusion of 13 patients. Patient demographics are shown in Table 1. All patients included in the study had untreated brain metastases at baseline. The median age of patients was 62 years. Of the 13 patients, seven patients (53.8%) were male, and six patients (46.2%) were female. Seven patients were never smokers, and four were current smokers. Non-squamous histology was identified in 11 patients, while squamous histology was observed in two patients. At baseline, all patients had an ECOG performance status of 0. Prior treatments included surgical resection in one patient, concurrent chemoradiotherapy in two patients, and radiotherapy alone in one patient. Two patients were treated with systemic chemotherapy prior to treatment as adjuvant or neoadjuvant therapy. At baseline nine patients (69.2%) exhibited multiple brain metastases, and four patients (30.8%) had sum of intracranial lesions with a maximum diameter of ≥ 20 mm. None of the enrolled patients were receiving corticosteroid for tumor control at the initiation of study treatment.

Table 1.

Baseline demographics

2. Clinical efficacy and survival analysis

The data cutoff date was 30 June 2024. In the FAS, the icORR was 46.2% (95% CI, 19.2 to 74.9) with six patients showing PR. The remaining five patients demonstrated stable disease (Table 2). Based on histologic subtype, six of 11 patients with non-squamous cell carcinoma (54.6%) achieved an objective response, whereas no objective responses were observed among patients with squamous cell carcinoma. The median icPFS was 9.8 months (95% CI, 5.2 to 21.5) with nine patients showing progression or death at the data-cutoff and the median icDoR was 9.3 months (95% CI, 4.0 to 20.3) (Fig. 1). Systemic ORR for the FAS was 46.2% (95% CI, 19.2 to 74.9). The median PFS was 7.2 months (95% CI, 2.4 to 12.3) and median OS of 10.7 months (95% CI, 7.2 to 21.5) (Fig. 2). All patients who achieved a systemic objective response also demonstrated an intracranial objective response. The degree of response is shown in Fig. 3. Among the six patients who achieved a partial response, one subsequently developed isolated central nervous system (CNS) progression, while three experienced extracranial progression. The remaining two patients discontinued treatment owing to other causes. The patient with isolated CNS progression later received WBRT. Of the three patients with extracranial progression, one underwent WBRT, and another received additional gamma knife surgery.

Table 2.

Intracranial efficacy outcomes

Fig. 1.

Intracranial progression-free survival (icPFS); median icPFS was 9.8 months (95% confidence interval, 5.2 to 21.5).

Fig. 2.

Progression-free survival (PFS) (A) and overall survival (OS) (B); median PFS was 7.2 months (95% confidence interval [CI], 2.4 to 12.3) and median OS was 10.7 months (95% CI, 7.2 to 21.5).

Fig. 3.

Waterfall plot showing best percentage change from baseline in intracranial and systemic target lesion size for each patient, representing the maximum tumor response.

3. Safety analysis

Most TRAEs were grade 1 or 2 in severity (Table 3). The most frequently reported TRAEs included elevations in alanine aminotransferase, aspartate aminotransferase, and pruritus. Grade ≥ 3 TRAEs included anemia and elevations in aspartate aminotransferase and alanine aminotransferase, occurring in a total of two patients (15.4%). No TRAEs of sufficient severity to necessitate treatment discontinuation or leading to death were reported during the study. No new safety signals emerged.

Table 3.

Treatment related adverse events

Discussion

This phase II study demonstrated that the combination of pembrolizumab and platinum-based chemotherapy achieved an icORR of 46%. The findings of our study are consistent with those of a previous phase II trial involving patients with NSCLC and brain metastases, which reported an icORR of approximately 30% following pembrolizumab monotherapy and 42.7% with atezolizumab with platinum-based chemotherapy in non-squamous NSCLC [11-13]. A similar icORR rate of 36% was also observed in a retrospective analysis of NSCLC patients in China [14]. Furthermore, subgroup analyses of pivotal trials investigating pembrolizumab in combination with platinum-based chemotherapy demonstrated an intracranial response of approximately 39% [13,15]. The results of the present study align well with these previously reported data. Additionally, like the previous studies, our data showed a high concordance rate of systemic response and intracranial response. However, a key distinction of our study is that, unlike other phase II trials, it specifically evaluated pembrolizumab in combination with platinum-based chemotherapy, which represents the most widely used regimen in advanced NSCLC. Moreover, the findings from other pivotal trials are derived solely from subgroup analyses rather than from studies specifically designed for patients with brain metastases. Notably, our results are also in accordance with the treatment approach recommended by the American Society of Clinical Oncology–Society for Neuro-Oncology–American Society for Radiation Oncology 2022 guidelines, which suggest that pembrolizumab may be offered to patients with asymptomatic brain metastases with a platinum agent [4]. While the efficacy of ICIs against brain metastases has traditionally been questioned, largely due to lack of pharmacokinetic or pharmacodynamic studies confirming that ICIs can penetrate into brain metastases through the blood-brain barrier (BBB) [16], emerging evidence suggests that ICIs can exert meaningful antitumor activity in this context. Two primary mechanisms have been proposed. First, systemically activated T cells may be recruited into the CNS, where they mediate immune responses against metastatic lesions [17]. Second, the ICIs themselves may cause disruption of the BBB, permitting direct penetration of anti–PD-1 antibodies into the CNS, thereby enabling these agents to modulate the tumor microenvironment locally [18]. Moreover, brain metastases themselves may lead to injury of astrocytes and microglial cells, which further compromises BBB integrity and facilitates the translocation of therapeutic antibodies across the barrier [19].

TRAEs were reported in most patients; however, most were tolerated and manageable. TRAEs deemed attributable to pembrolizumab and chemotherapy occurred in five patients (38.5%). Importantly, no cases of brain pseudoprogression or subsequent neurological TRAEs were observed. The overall safety profile observed in this study is consistent with previously published data on this therapeutic combination.

Major strength of this study is that it demonstrated the potential effectiveness of ICI combined with chemotherapy as a viable treatment option even in patients with previously untreated brain metastases, a situation in which limited data have been reported to date. Although a direct comparison with other studies is not feasible, considering the platinum-based chemotherapy showed objective response of 20% in patients with brain metastases, the intracranial response rate exceeding 40% in our study suggests a potentially meaningful therapeutic activity [15]. Limitations of this study include the small sample size, resulting from early termination of patient enrollment due to accrual challenges, and its single-arm design. Given that only 13 patients were enrolled out of the originally planned 50, this analysis should be interpreted with caution. In addition, the inclusion of only asymptomatic patients with ECOG performance status 0 may have introduced potential selection bias. Furthermore, PD-L1 status was not available for all patients, as some patients had undergone diagnostic biopsy at outside institutions, while others underwent biopsy from sites where adequate tissue acquisition was technically challenging. The limited sample size also precluded meaningful stratified analyses according to PD-L1 expression. Consequently, the optimal therapeutic strategy for NSCLC patients with untreated brain metastases at initial diagnosis without targetable oncogene remains unclear. Further randomized clinical trials are warranted to determine the most appropriate timing and integration of brain-directed local therapies, particularly in patients with minimal neurological symptoms.

In conclusion, pembrolizumab in combination with platinum-based chemotherapy has activity in patients with treatment-naïve NSCLC with untreated brain metastases at diagnosis. Brain metastases showed a reasonable response rate with a tolerable side effect profile. Future studies warrant optimal treatment schemes for this vulnerable patient group.

Electronic Supplementary Material

Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).

crt_25-1100_Supplementary-Methods.pdf

Notes

Ethical Statement

The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonisation guideline for Good Clinical Practice. Independent ethics committees or institutional review boards of Samsung Medical Center (IRB approval number, 2021-06-008) approved the trial. All patients provided written informed consent. The trial is registered at ClinicalTrials.gov (NCT04967417).

Author Contributions

Conceived and designed the analysis: Park S, Jung HA, Sun JM, Lee SH, Ahn JS, Shin SH, Lee K, Um SW, Ahn MJ.

Collected the data: Kim J, Park S, Ahn MJ.

Contributed data or analysis tools: Han M, Kim J, Park S, Ahn MJ.

Performed the analysis: Kim J, Park S, Ahn MJ.

Wrote the paper: Kim JK, Ahn MJ.

Conflicts of Interest

Conflict of interest relevant to this article was not reported.

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Article information Continued

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Characteristic	No. (%) (n=13)
Age (yr), median (range)	62 (32-82)
Sex
Male	7 (53.8)
Female	6 (46.2)
Smoking
Never	7 (53.8)
Former	2 (15.4)
Current	4 (30.8)
ECOG performance status
0	13 (100)
1	NA
PD-L1 tumor proportion score (%)
< 1	5 (38.5)
1-49	2 (15.4)
≥ 50	4 (30.8)
Unknown	2 (15.4)
Pathology subtype
Non-squamous cell carcinoma	11 (84.6)
Squamous cell carcinoma	2 (15.4)
Previous treatment
Surgery	1 (7.7)
Radiotherapy	3 (23.1)
CCRT	2 (15.4)
Systemic chemotherapy	2 (15.4)
Stage
IVa	3 (23.1)
IVb	10 (76.9)
Distant metastasis site
Lung	4 (30.8)
Liver	2 (15.4)
Distant metastatic lymph node	1 (7.7)
Bone	6 (46.2)
Brain	13 (100)
Single	4 (30.8)
Multiple	9 (69.2)
Size of primary CNS lesion (mm)
≥ 20	4 (30.8)
< 20	9 (69.2)

Category	Total (FAS)
Category	No. (%) (n=13)
Best overall response	13 (100)
Complete response	0
Partial response	6 (46.2)
Stable disease	5 (38.5)
Progressive disease	1 (7.7)
Not evaluable	1 (7.7)
CR or PR	6 (46.2)
Intracranial ORR (95% CI) (%)	46.2 (19.2-74.9)

Adverse events	Any grade	Grade 3, 4
Overall	5 (38.5)	2 (15.4)
Anemia	1 (7.7)	1 (7.7)
Alanine aminotransferase elevation	2 (15.4)	1 (7.7)
Aspartate aminotransferase elevation	2 (15.4)	1 (7.7)
Pruritus	2 (15.4)	0
Rash	1 (7.7)	0
Nausea	1 (7.7)	0
Edema	1 (7.7)	0
Blood creatinine increased	1 (7.7)	0
Fatigue	1 (7.7)	0