Phase II Study of Cisplatin/Gemcitabine Plus Necitumumab for Squamous NSCLC After ICI‐Platinum Therapy (WJOG14120L)

ABSTRACT

Treatment options remain limited for unresectable or advanced lung squamous cell carcinoma (LSqCC) that progresses after immune checkpoint inhibitor (ICI)‐based therapy. Although combination therapy with cisplatin, gemcitabine, and necitumumab (CGN) represents a potential second‐line regimen, no prospective data in a post‐ICI setting have been reported. This open‐label, multicenter single‐arm Phase II study enrolled patients with LSqCC after platinum‐based chemotherapy plus ICI, including concurrent chemoradiotherapy. The primary endpoint was objective response rate (ORR), with the null and alternative hypotheses set at 23% and 40%, respectively. Secondary endpoints included the disease‐control rate (DCR), progression‐free survival (PFS), overall survival (OS), the impact of platinum‐free interval (PFI), eligibility for anti‐angiogenic therapies, and safety. Forty‐six patients were evaluable for efficacy. ORR was 26.1% (80% CI, 17.7–36.2) and DCR was 87.0% (95% CI, 73.7–95.1). Median PFS and OS were 4.4 months (95% CI, 4.1–5.5) and 12.2 months (95% CI, 9.4–15.2), respectively. Common adverse events included hematological toxicities, acneiform rash, and hypomagnesemia. No pneumonitis or treatment‐related deaths were observed. The safety profile was consistent across prior treatment types and anti‐angiogenic therapies eligibility. PFI analysis showed that longer PFI durations were associated with improvements in PFS and OS, and the optimal PFI cutoff value was approximately 4 months. Although the predefined response threshold was not met, CGN demonstrated modest antitumor activity with a high DCR and a manageable toxicity after ICI‐based therapy. CGN may be a feasible treatment option for second‐line after ICI‐based therapy, including for patients unsuitable for anti‐angiogenic therapies, although further validation is warranted.

Trial Registration: jRCTs051200138

WJOG14120L NESSIE evaluated cisplatin, gemcitabine, and necitumumab (CGN) as second‐line therapy after ICI‐based treatment in 46 patients with advanced squamous NSCLC. ORR was 26.1%, DCR 87.0%, and median PFS 4.4 months. Although the predefined ORR threshold was not met, CGN showed modest antitumor activity with manageable toxicity. A longer platinum‐free interval was associated with improved PFS, OS, and ORR. CGN may be a feasible second‐line option after ICI‐based therapy.

Abbreviations

AE

adverse event

CGN

cisplatin, gemcitabine, and necitumumab

CI

confidence interval

CRT

chemoradiotherapy

DCR

disease‐control rate

EGFR

epidermal growth factor receptor

ICI

immune checkpoint inhibitor

LSqCC

lung squamous cell carcinoma

NSCLC

non‐small cell lung cancer

ORR

objective response rate

OS

overall survival

PBC

platinum‐based chemotherapy

PFI

platinum‐free interval

PFS

progression‐free survival

PS

performance status

ROC

receiver operating characteristic

1. Introduction

Lung cancer is the leading cause of cancer‐related mortality worldwide [1]. In Japan, lung cancer is the second most common cancer after colorectal cancer and the leading cause of cancer deaths, with an estimated 82,700 cases in men and 41,700 in women in 2021, and an estimated 52,900 deaths in men (the leading cause of cancer death) and 22,800 in women (the second leading cause of cancer death) [2].

Non‐small cell lung cancer (NSCLC) is classified into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma according to its histological type. Squamous cell carcinoma is the second most common type of lung cancer after adenocarcinoma, accounting for about 40% of all lung cancers in men, 15% in women, and 30% overall. The choice of treatment for advanced NSCLC is based on factors such as the patient's performance status (PS), histology, and type of genetic mutation. Treatment with pemetrexed or bevacizumab is not recommended for patients with lung squamous cell carcinoma (LSqCC), in terms of its efficacy and toxicity (Lung Cancer Clinical Practice Guidelines, 2019) [3]. In addition, driver gene mutations such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase gene translocations are rare in LSqCC, it is therefore unlikely to be treated with agents such as EGFR tyrosine kinase inhibitors and anaplastic lymphoma kinase inhibitors that target these gene mutations. Patients with LSqCC thus have limited treatment options compared with patients with non‐LSqCC.

Immune checkpoint inhibitor (ICI) has recently become available for the treatment of advanced or recurrent NSCLC, and their efficacy, either alone or in combination with platinum‐based chemotherapy (PBC), has been indicated in LSqCC. The initial standard treatment for Stage IV LSqCC is a three‐drug combination therapy; combination immunotherapy consisting of ICIs and PBC [4]. Additionally, the standard treatment for unresectable localized LSqCC is PBC combined with radiation followed by durvalumab as maintenance therapy [5]. However, second‐line therapy for patients with progressive disease after initial treatment with ICI has not been established, and the combination of docetaxel and ramucirumab is often considered as the standard second‐line therapy after initial treatment [6].

The REVEL study in patients initially treated with PBC found that docetaxel plus ramucirumab therapy was significantly superior to docetaxel alone in terms of overall survival (OS) [7]. However, docetaxel plus ramucirumab therapy is only applicable for select patients who are eligible for anti‐angiogenic therapies, and docetaxel alone therefore remains the standard second‐line treatment for patients who are ineligible for anti‐angiogenic therapies.

A previous prospective study and several retrospective studies have reported on the efficacy and safety of second‐line treatment with docetaxel and ramucirumab after first‐line treatment regimens using ICI [8, 9, 10, 11]. These results indicated that the efficacy of docetaxel plus ramucirumab therapy was maintained even in cases when an ICI was added to the initial treatment regimen for NSCLC; however, these studies included limited data on LSqCC and post‐chemoradiotherapy (CRT) treatment. There is thus a lack of data regarding second‐line treatment after initial treatment with ICI, and the treatment of LSqCC remains clinically challenging because of concerns of life‐threatening pulmonary hemorrhage in some patients [12, 13, 14]. It is therefore necessary to consider treatment options for patients who are ineligible for docetaxel and ramucirumab therapy.

Necitumumab is a second‐generation, recombinant, human IgG1 EGFR monoclonal antibody that binds to EGFR with high affinity, thereby preventing receptor activation and activation of downstream signaling pathways. Necitumumab plus gemcitabine and cisplatin (CGN) therapy is indicated as a standard treatment regimen in the Guidelines for Diagnosis and Treatment of the Lung Cancer issued by the Japan Lung Cancer Society [3]. A recent retrospective study (NINJA study) reported CGN to be a potential treatment option in patients with LSqCC after initial treatment including ICI [15].

The current prospective study aimed to assess the efficacy and safety of CGN therapy in patients with unresectable or recurrent LSqCC after initial treatment including ICI with PBC, including CRT. Subgroup analyses in this study compared the efficacy and safety of CGN following two types of initial treatment (ICI with PBC or CRT with PBC followed by ICI), and between patients eligible for anti‐angiogenic therapies and those ineligible for these drugs. Additionally, because platinum‐free interval (PFI) is considered a potential indicator of sensitivity to platinum rechallenge, this study prospectively evaluated the association between PFI and treatment efficacy according to a pre‐specified protocol.

2. Material and Methods

2.1. Study Design

The WJOG14120L NESSIE study was a single‐arm, multicenter, Phase II study conducted at 33 institutions in Japan (Japan Registry of Clinical Trials: jRCTs051200138). Eligible patients were aged ≥ 20 years and had an Eastern Cooperative Oncology Group PS of 0 or 1 and pathologically confirmed unresectable or advanced LSqCC after initial treatment with ICI plus PBC, including concurrent CRT. Patients with a history of radiation therapy including the lung in the irradiation field who had stable Grade 1 radiation pneumonitis were considered eligible. Subgroup analysis was conducted in patients eligible and ineligible for anti‐angiogenic therapies, based on the criteria predefined in the protocol. The detailed inclusion and exclusion criteria are provided in Document S1.

2.2. Procedure

CGN (cisplatin 75 mg/m² on Day 1, gemcitabine 1250 mg/m² on Days 1 and 8 for up to four cycles, and necitumumab 800 mg on Days 1 and 8 of each 21‐day cycle, continued as monotherapy maintenance therapy after cycle 4) was administered until progressive disease or unacceptable toxicity. The cisplatin dose of 75 mg/m² was selected as the approved dose based on previous studies [16, 17]. Necitumumab was administered 1 h before cisplatin and gemcitabine administration. Dose modifications of the study drugs were allowed in accordance with the severity of adverse events (AEs). The criteria for treatment delay and/or dose reduction are shown in Document S2. Tumor response was assessed every 6 weeks up to 6 months from the start of the protocol treatment, and once every 9 weeks thereafter. AEs were assessed throughout the study treatment period and until improvement of treatment‐related AEs. Severe AEs were also reported during study treatment. The efficacy endpoints were evaluated mainly in the per‐protocol set and the safety endpoints were evaluated in the full‐analysis set.

2.3. Outcomes

The primary endpoint was the objective response rate (ORR), defined as the best complete response or partial response according to RECIST version 1.1. Secondary endpoints were the disease‐control rate (DCR), progression‐free survival (PFS), OS, relationships between efficacy and PFI and between efficacy and patient characteristics (e.g., eligibility for anti‐angiogenic therapies use or type of initial treatment), treatment feasibility (e.g., number of treatment courses, dose interruption/reduction, dose‐intensity), and AEs graded according to the Common Terminology Criteria for Adverse Events version 5.0.

The eligibility for anti‐angiogenic therapies use at baseline was evaluated by the study investigators based on the patient's condition using the following definitions: no invasion of major blood vessels or stenosis of major blood vessels due to cancer; no intratumoral cavities observed on imaging tests; no tumor exposure to the central airway up to segmental branches (determination based on imaging tests is acceptable); no history of radiation therapy, including palliative radiation therapy to the mediastinum; and no bloody sputum exceeding 5 mL within 28 days prior to enrollment. Patients who met all these criteria were considered eligible for anti‐angiogenic therapies use.

2.4. Statistical Analysis

The full‐analysis set included all patients who received at least one dose of study treatment. The per‐protocol set, which was prespecified as the primary efficacy analysis population, excluded patients with major deviations that could affect efficacy assessment.

A previous Japanese Phase II study found a 51.1% response rate in the CGN arm in chemotherapy‐naïve patients [17]. The expected response rate was therefore set at 40%, considering the possibility that the response rate may be lower because of second‐line treatment and the re‐challenge of platinum agents. The Phase III REVEL study [4] comparing docetaxel plus ramucirumab with docetaxel as second‐line treatment after PBC found a response rate for docetaxel plus ramucirumab of 22.9% (95% confidence interval [CI] 19.7%–26.4%) in patients with NSCLC, and a response rate of 26.8% (95% CI 20.0–34.4) in the LSqCC subgroup. In a randomized Phase II study (JVGC) conducted in Japan, the response rate of docetaxel plus ramucirumab was 28.9% (95% CI 19.1–40.5) [18]. The proportion of LSqCC in the REVEL and JVGC studies was 26.1% and 11.5%, respectively [4, 18]. In the current NESSIE study, the threshold response rate was set at 23%, which exceeded the results of the REVEL and JVGC studies for second‐line treatment after PBC therapy [4, 18]. The binomial analysis set for the null hypothesis had an ORR of 23% and an alternative of 40% with a one‐sided α of 0.1 and a power of 80%, because of the exploratory nature of the study. Consistent with the one‐sided α of 0.10, the 80% CI for ORR was calculated for the primary analysis. Accordingly, the target accrual size was 41 patients. Allowing for a potential drop‐out rate of 10%, we planned to enroll a total of 45 patients. Binomial CIs were estimated for ORR and DCR using the exact method. Time‐to‐event analyses were calculated for PFS and OS using the Kaplan–Meier method and compared using the log‐rank test.

Subgroup analyses for ORR were conducted using univariate logistic regression models. The relationship between ORR and baseline patient characteristics, including PFI cutoff of 30, 60, 90, 120, and 180 days, as well as the median PFI was evaluated. In addition, the optimal PFI cutoff value for predicting ORR was determined using receiver operating characteristic (ROC) curve analysis.

For PFS and OS, optimal cutoff values were determined using the minimum p‐value method to account for censored observations. Candidate cutoff values across the observed range of PFI were evaluated, and the cutoff yielding the smallest log‐rank p value was selected. Associations between PFI and PFS or OS were also evaluated using cutoff values at predefined PFI time points (30, 60, 90, 120, 180 days, and median PFI). Survival curves for PFS and OS were estimated using the Kaplan–Meier method and compared using the log‐rank test.

Patients were divided into two groups according to their eligibility for anti‐angiogenic therapies use at baseline, and the relationships between efficacy and eligibility for anti‐angiogenic therapies were examined. Survival curves for PFS and OS were estimated using the Kaplan–Meier method.

In addition, we evaluated the relationships between efficacy and the prior therapy regimen type (PBC with ICI or CRT followed by ICI). Survival curves for PFS and OS were estimated using the Kaplan–Meier method.

SAS System version 9.4 (SAS Institute Inc., Cary, NC, USA) software was used to conduct all statistical analyses.

The study protocol was approved by Wakayama Medical University Clinical Research Ethical Committee (CRB5180004, Date: January 20, 2021). This study was carried out in accordance with the international ethical recommendations stated in the Declaration of Helsinki and the Japanese Ethical Guidelines for Clinical Research. All patients who were enrolled in this study provided written informed consent to participate in the study.

3. Results

3.1. Patients

Forty‐seven patients who received initial treatment with ICIs plus PBC or PBC containing CRT followed by ICI were enrolled between February 2021 and April 2023. The data cutoff date was October 2024. Forty‐six patients met the eligibility criteria. The remaining patient was found after registration to have primary adrenal cancer that met the exclusion criteria and was therefore excluded from the per‐protocol efficacy analysis. The baseline patient characteristics are shown in Table 1.

TABLE 1.

Patient demographics and clinical characteristics at baseline.

Characteristics (n = 46)	n (%)
Age, years
< 65	12 (26.1)
≥ 65	34 (73.9)
Median, years (range)	68 (52–78)
Sex
Male	42 (91.3)
Female	4 (8.7)
Smoking status a
Never	2 (4.3)
Past	19 (41.3)
Current	25 (54.3)
ECOG PS
0	16 (34.8)
1	30 (65.2)
Clinical stage (at the start of prior treatment)
Recurrence after local therapies b	6 (13.0)
III	16 (34.8)
IV	24 (52.2)
First‐line platinum CT/CRT
CRT followed by ICI	16 (34.8)
PBC + ICI	30 (65.2)
Metastatic sites at baseline
Pleura/Pleural effusion	23 (50.0)
Bone	13 (28.3)
Lung	8 (17.4)
Liver	8 (17.4)
Brain	4 (8.7)
Lymph nodes	4 (8.7)
Adrenal gland	3 (6.5)
Kidney	3 (6.5)
Chest wall	1 (2.2)
Eligible for anti‐angiogenic therapies c
Eligible	24 (52.2)
Ineligible	22 (47.8)
Platinum‐free interval d
Median, days (range)	221 (23–728)
Immunotherapy‐free interval
Median, days (range)	43 (21–685)

Abbreviations: CRT, chemoradiotherapy; CT, chemotherapy; ICI, immune checkpoint inhibitor; PBC, platinum‐based chemotherapy; PS, performance status.

^a Smoking status (never, < 100 cigarettes in all life; past, ≥ 100 in all life, but no smoking within 1 year; current, ≥ 100 in all life, but smoking within 1 year).

^b Among the six patients classified as recurrence after local therapy, four had previously received surgery and two had previously received stereotactic body radiotherapy for clinical Stage I–IIA NSCLC.

^c Eligible for anti‐angiogenic therapies according to criteria described in Patients and Methods.

^d PFI defined as the period from 3 weeks after the last administration of platinum in prior combination immunotherapy (same day of the week) to the start of administration of the clinical study drugs.

The median PFI was 221 days (range: 23–728 days).

The median number of treatment cycles for CGN was six (range: 1–14), and the dose intensities of cisplatin, gemcitabine, and necitumumab were 77.9% (50.7%–104%), 68.1% (42.8%–92.3%), and 75.0% (40.2%–95.5%), respectively (Tables S1 and S2). Treatment was discontinued in 97.8% (45/46) of patients at cutoff date with 37 of 45 (82.2%) discontinuing treatment because of progressive disease, seven (15.6%) because of AEs, and one patient (2.2%) who died during treatment. Thirty‐six of the 46 patients (78.3%) received post‐treatment for CGN, including 11 patients (23.9%) who received docetaxel and ramucirumab, seven (15.2%) who received docetaxel, and seven (15.2%) who received S‐1 (Table S3).

3.2. Efficacy

Twelve of the 46 patients assessable for efficacy achieved an objective response. The ORR and DCR were 26.1% (80% CI 17.7%–36.2%, 95% CI 14.3–41.1) and 87.0% (95% CI 73.7–95.1), respectively. Similar results were observed in the full‐analysis set (n = 47), including one protocol‐ineligible patient in which the ORR was 25.5% (12/47; 95% CI 13.9–40.3).

A waterfall plot is shown in Figure 1. After a median follow‐up period of 29.3 months (reverse Kaplan–Meier method) the median PFS and OS were 4.4 months (95% CI, 4.1–5.5) and 12.2 months (95% CI, 9.4–15.2), respectively (Table 2) (Figure 2A,B).

FIGURE 1.

Waterfall plot showing best percentage change in tumor burden. One patient was excluded because no imaging study was done. CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease.

TABLE 2.

Objective response.

Response (n = 46)	n (%)
CR	0
PR	12 (26.1)
SD	28 (60.9)
PD	4 (8.7)
NE	2 (4.3)
ORR (CR + PR) (%)	12 (26.1)
80% CI (two‐sided)	17.7–36.2
95% CI (two‐sided)	14.3–41.1
DCR (CR + PR + SD) (%)	40 (87.0%)
95% CI (two‐sided)	73.7–95.1

Abbreviations: CI, confidence interval; CR, complete response; DCR, disease‐control rate; NE, not evaluable; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.

FIGURE 2.

Kaplan–Meier survival curves showing the progression‐free survival and overall survival. Kaplan–Meier survival curves showing progression‐free survival (A) and overall survival (B) for all patients. For PFI analyses, patients were stratified using the optimal cutoff values identified by the prespecified minimum p‐value method. Progression‐free survival is shown according to a cutoff value of 133 days (C), and overall survival according to a cutoff value of 110 days (D). CI, confidence interval; PFI, platinum‐free interval; mOS, median overall survival; mPFS, median progression‐free survival.

Subgroup analyses of factors associated with ORR showed no significant association between baseline patient characteristics and ORR (Table S4). However, using the ROC‐derived PFI cutoff value of 352 days, patients with a longer PFI had a higher ORR than those with a shorter PFI (55.6% vs. 18.9%; OR 5.36, 95% CI 1.14–25.26; p = 0.034).

In analyses of survival outcome, the optimal PFI cutoff values determined by the minimum p‐value method were 133 days for PFS and 110 days for OS. A longer PFI was significantly associated with prolonged PFS (median, 5.3 vs. 4.1 months; p = 0.0055) and OS (median, 14.3 vs. 7.6 months, p = 0.0012) (Figure 2C,D). The effects of PFI evaluated at predefined time points and at the optimal cutoff values are summarized in Tables S5 and S6.

In the subgroup analysis according to eligibility for anti‐angiogenic therapies use at baseline, there was no significant difference in median PFS (ineligible: 5.4, eligible: 4.1 months, p = 0.238) or median OS (ineligible: 14.2, eligible: 8.8 months, p = 0.161) (Figure S1). Additionally, the subgroup analysis in patients who received PBC with ICIs according to eligibility for anti‐angiogenic therapies use at baseline is shown in Figure S2.

Subgroup analysis according to type of prior therapies (CRT followed by ICI or PBC with ICI) also showed no significant association with median PFS (CRT followed by ICI: 5.5, PBC with ICI: 4.2 months, p = 0.456) or median OS (CRT followed by ICI: 14.2, PBC with ICI: 10.6 months, p = 0.461) (Figure S3).

3.3. Safety

Safety data were available for all 47 patients. The most common AEs of any grade were acneiform rash (68.1%), hypomagnesemia (51.1%), neutropenia (63.8%), leukocytopenia (55.3%), and thrombocytopenia (55.3%). Grade 3 or 4 AEs occurring in > 10% of patients included neutropenia (46.8%), thrombocytopenia (34.0%), leukocytopenia (29.8%), febrile neutropenia (14.3%), anemia (12.8%), pulmonary infection (10.6%), and acneiform rash (10.6%) (Table 3). Peripheral neuropathy was observed in three patients (6.4%). No treatment‐related deaths were observed. Although patients with Grade 1 or lower radiation pneumonitis with stable disease at enrollment were eligible, no interstitial pneumonitis or worsening of radiation pneumonitis was observed. Among the 16 patients who had previously received definitive chemoradiotherapy, one had radiation pneumonitis at enrollment. Thromboembolic events were observed in three patients (6.4%), including two Grade 2 events and one Grade 3 event (pulmonary embolism).

TABLE 3.

Treatment‐emergent adverse events ≥ 20%.

AEs (n = 47)	Any grade	≥Grade 3	Grade 1	Grade 2	Grade 3	Grade 4
	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)
Hematologic AEs
Neutropenia	30 (63.8)	22 (46.8)	2 (4.3)	6 (12.8)	11 (23.4)	11 (23.4)
Leukopenia	26 (55.3)	14 (29.8)	4 (8.5)	8 (17.0)	9 (19.1)	5 (10.6)
Thrombocytopenia	26 (55.3)	16 (34.0)	3 (6.4)	7 (14.9)	11 (23.4)	5 (10.6)
Non‐hematologic AEs
Rash acneiform	32 (68.1)	5 (10.6)	15 (31.9)	12 (25.5)	5 (10.6)	0
Hypomagnesemia	24 (51.1)	2 (4.3)	13 (27.7)	9 (19.1)	1 (2.1)	1 (2.1)
Anemia	21 (44.7)	6 (12.8)	9 (19.1)	6 (12.8)	6 (12.8)	0
Constipation	15 (31.9)	0	8 (17.0)	7 (14.9)	0	0
Decrease appetite	14 (29.8)	0	11 (23.4)	3 (6.4)	0	0
Dry skin	14 (29.8)	0	7 (14.9)	7 (14.9)	0	0
Malaise	13 (27.7)	0	9 (19.1)	4 (8.5)	0	0
Albumin decreased	12 (25.5)	0	5 (10.6)	7 (14.9)	0	0
Paronychia	11 (23.4)	0	9 (19.1)	2 (4.3)	0	0
Nausea	11 (23.4)	0	7 (14.9)	4 (8.5)	0	0
ALT increased	10 (21.3)	0	9 (19.1)	1 (2.1)	0	0
Mucositis	10 (21.3)	0	4 (8.5)	6 (12.8)	0	0
Hyponatremia	10 (21.3)	1 (2.1)	8 (17.0)	1 (2.1)	1 (2.1)	0

Note: Grade 3 or 4 AEs observed in ≥ 2 patients (AEs not listed in the table above) included pulmonary infection (n = 5, 10%) and febrile neutropenia (n = 7, 14.9%).

Abbreviations: AE, adverse event; ALT, alanine aminotransferase.

There was no significant difference in the safety of CGN therapy between patients who were eligible or were ineligible for anti‐angiogenic therapies at baseline (Table S7), or between patients with different prior therapies (PBC with ICI or CRT followed by ICI) (Table S8).

4. Discussion

The NESSIE study is the first prospective evaluation of CGN as second‐line therapy in unresectable or recurrent LSqCC that progresses after ICI‐based treatment, including concurrent CRT. Given the limited clinical data available for this increasingly common post‐ICI treatment setting, our findings provide insights into the efficacy, safety, and potential positioning of CGN in LSqCC treatment.

The primary endpoint, overall response rate (ORR), was 26.1% (80% CI 17.7%–36.2%), which did not exceed the predefined threshold response rate. However, CGN showed a high DCR of 87.0% (95% CI 73.7–95.1), along with a favorable median PFS of 4.4 months (95% CI 4.1–5.5 months) and median OS of 12.2 months (95% CI 9.4–15.2 months). Furthermore, the high transition rate to subsequent therapy indicates that CGN does not hinder progression to further treatment. These findings suggest that CGN may provide a feasible treatment option for selected patients with LSqCC in the second line setting, where therapeutic choices remain limited.

The efficacy results of the NESSIE study were consistent with those of the previously conducted retrospective study, the NINJA study, which evaluated CGN therapy after first‐line ICI‐based regimens (NINJA study: ORR, 27.3% [95% CI, 18.3–37.8]; median PFS, 4.4 months [95% CI, 3.8–5.3 months]; median OS, 13.3 months [95% CI, 9.6–16.5 months]; rate of transition to subsequent therapy, 69.9%) [15].

A key finding of the NESSIE study is the association between PFI and treatment outcomes. Patients with a longer PFI demonstrated significantly improved PFS and OS compared with those with a shorter PFI. Although the optimal cutoff for PFI remains unclear, these findings suggest that PFI may serve as a practical indicator for identifying patients who are more likely to benefit from the CGN regimen, a broad form of platinum rechallenge.

While the clinical significance of PFI in platinum rechallenge is well established in ovarian cancer and small cell lung cancer [19, 20, 21], it has not been fully elucidated in NSCLC. Several retrospective studies in NSCLC have evaluated the prognostic value of PFI in the context of platinum rechallenge and have reported that a longer PFI is associated with improved OS [22, 23]. In the retrospective NINJA study, which included patients treated with CGN after ICI‐based therapy, the relationship between PFI and efficacy was assessed using a cutoff of 6 months, and patients with a PFI of ≥ 6 months exhibited improved PFS [16].

As combination therapy with ICIs and PBC is increasingly being used as a standard first‐line treatment, platinum rechallenge is becoming an option in the second‐line setting. In this treatment setting, the application of simple and clinically practical predictive factors such as PFI will be highly important in routine clinical practice. The safety profile observed in the NESSIE study was consistent with the safety profiles of CGN reported in first‐line studies and in the retrospective NINJA study. Importantly, despite prior exposure to ICI‐based combination therapy, including concurrent CRT followed by consolidation ICI, no increase in immune‐related AEs or pneumonitis was observed.

These findings may provide clinical usefulness and suggest a feasible therapeutic option in settings where treatment choices are often limited due to concerns about pulmonary toxicity in patients with a past history of radiation pneumonitis or side effects from ICIs.

This finding may be relevant in LSqCC, where the risk of pulmonary hemorrhage or vascular complications often precludes the use of anti‐angiogenic therapies. CGN may provide a clinically meaningful alternative for these patients.

The NESSIE study had several limitations. First, the NESSIE study employed a single‐arm design, making it difficult to adequately evaluate the comparisons with other second‐line treatment regimens. Second, the sample size was small.

Although the study suggested the potential clinical utility of CGN therapy in the optimal cutoff value of PFI, the PFI cutoff values were derived using ROC and minimum p‐value methods which may be subject to multiplicity and overfitting. Therefore, these findings should be considered hypothesis‐generating and require external validation in larger cohorts. Third, biomarker analyses were not performed. EGFR expression on tumor cells is highly prevalent in LSqCC and some studies have suggested an association between the level of EGFR expression and the efficacy of anti‐EGFR antibodies. Further investigation into biomarker‐based patient selection remains an important area for future research.

This study provides prospective data on the use of CGN after ICI‐based therapy in patients with LSqCC. Although the primary endpoint was not met, CGN demonstrated modest antitumor activity, a high DCR, and manageable toxicity. In view of the limited treatment options available for LSqCC, CGN may be a feasible treatment option for select patients. However, these findings should be interpreted with caution and require validation in larger studies. A graphical overview of the present study is presented in Figure 3.

FIGURE 3.

Graphical summary of the study.

Author Contributions

Hiroshige Yoshioka: conceptualization, funding acquisition, investigation, methodology, project administration, resources, supervision, validation, writing – original draft, writing – review and editing. Keita Mori: conceptualization, data curation, formal analysis, methodology, supervision, validation, visualization, writing – review and editing. Nobuhisa Ishikawa: investigation, resources, writing – review and editing. Hiroaki Kanemura: investigation, resources, writing – review and editing. Koichi Azuma: investigation, resources, writing – review and editing. Yukihiro Toi: investigation, resources, writing – review and editing. Hiroshi Handa: investigation, resources, writing – review and editing. Yosuke Tamura: investigation, resources, writing – review and editing. Hiroaki Akamatsu: investigation, resources, writing – review and editing. Haruko Daga: investigation, resources, writing – review and editing. Masafumi Yamaguchi: investigation, resources, writing – review and editing. Teppei Yamaguchi: investigation, resources, writing – review and editing. Yuki Sato: investigation, resources, writing – review and editing. Nobuyuki Yamamoto: writing – review and editing, investigation, resources, supervision. Kazuhiko Nakagawa: investigation, writing – review and editing, supervision, resources. Takayasu Kurata: conceptualization, investigation, resources, supervision, validation, writing – review and editing.

Funding

This work was supported by the Nippon Kayaku Co. Ltd. Nippon Kayaku Co. Ltd. had no role in the design, analysis, or interpretation of the results in this study. Nippon Kayaku Co. Ltd. was given the opportunity to review the abstract.

Ethics Statement

The study protocol was approved by Wakayama Medical University Clinical Research Ethical Committee (CRB5180004; date: January 20, 2021). The study was registered in the Japan Registry of Clinical Trials (jRCTs051200138). This study was carried out in accordance with the international ethical recommendations stated in the Declaration of Helsinki and the Japanese Ethical Guidelines for Clinical Research. All patients who were enrolled in this study provided written informed consent to participate in the study.

Conflicts of Interest

H.Y. reports research funding to institution by MSD, Daiichi Sankyo, Janssen, and Regeneron; consulting fees from Delta Fly Pharmaceutical; and honoraria for lectures from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Kyowa Kirin, Merck Biopharma, MSD, Nippon Kayaku, Novartis, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Regeneron, Taiho Pharmaceutical, Takeda Pharmaceutical, and Janssen. K.M. reports statistical consultancy fees from Daiichi Sankyo; and payment for lectures including service on speakers bureaus from Eli Lilly, Chugai Pharmaceutical, and Ono Pharmaceutical. N.I. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Nippon Kayaku and AstraZeneca. H.K. reports grants to institution from Chugai Pharmaceutical and Takeda Pharmaceutical; and honoraria for lectures from Chugai Pharmaceutical, AstraZeneca, Daiichi Sankyo, MSD, and Novartis. K.A. reports grants to institution from MSD, Janssen, Bristol Myers Squibb, AstraZeneca, Taiho Pharmaceutical, Amgen, Daiichi Sankyo, IQVIA, EPS, and Syneos Health; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, MSD, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, Takeda Pharmaceutical, Taiho Pharmaceutical, Amgen, and Johnson & Johnson. YTo reports honoraria from Ono Pharmaceutical, Bristol Myers Squibb, MSD, Chugai Pharmaceutical, AstraZeneca, and Taiho Pharmaceutical. YTa reports research funding to institution by Ono Pharmaceutical; and payment of honoraria for lectures from AstraZeneca, Ono Pharmaceutical, MSD, and Chugai Pharmaceutical. H.A. reports grants from Amgen, Chugai Pharmaceutical, Novartis, and MSD; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen, AstraZeneca, Boehringer Ingelheim Japan, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Janssen, MSD, Nippon Kayaku, Novartis, Ono Pharmaceutical, Pfizer, Takeda Pharmaceutical, and Taiho Pharmaceutical; and participation on a Data Safety Monitoring Board or Advisory Board of Amgen, Janssen, GSK, and Sandoz. M.Y. reports grants to institution from AstraZeneca, BioNTech SE, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Genmab, MSD, Pfizer Japan, Taiho Pharmaceutical, and Takeda Pharmaceutical; and honoraria for lectures from Amgen, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, Janssen, Johnson & Johnson, Merck Biophama, MSD, Nippon Kayaku, Ono Pharmaceutical, Taiho Pharmaceutical, and Takeda Pharmaceutical. T.Y. reports honoraria for lectures from AstraZeneca, Novartis, Boehringer Ingelheim, Bristol Myers Squibb, Ono Pharmaceutical, Takeda Pharmaceutical, Chugai Pharmaceutical, Pfizer, Taiho Pharmaceutical, MSD, Janssen, Nippon Kayaku, and Daiichi Sankyo; and payment for advisory role from Daiichi Sankyo. Y.S. reports consulting fees from Novocure; honoraria from AstraZeneca, MSD, Novartis, Chugai Pharmaceutical, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Nippon Kayaku, Bristol Myers Squibb, Eli Lilly, Takeda Pharmaceutical, Kyowa Kirin, Daiichi Sankyo, Boehringer Ingelheim, Janssen, and Regeneron; and support for travel from Regeneron. N.Y. reports grants to institution from AstraZeneca, Chugai Pharmaceutical, MSD, Taiho Pharmaceutical, Boehringer Ingelheim, Novartis, Abbvie, Amgen, Asahi Kasei, Janssen, Bristol Myers Squibb Japan, IQVIA, EPS, A2 Healthcare, Mebix, Ono Pharmaceutical, Nippon Kayaku, Medical Market Vision, Syneos Health, Medpace Japan, Eli Lilly Japan, GSK, and Kyowa Kirin; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Chugai Pharmaceutical, MSD, Takeda Pharmaceutical, Accuray, Abbvie, Amgen, Ono Pharmaceutical, Guardant Health, Kyorin Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Tsumura, TERUMO, Eli Lilly Japan, Boehringer Ingelheim, Novartis, Pfizer, Miyarisan Pharmaceutical, Merck Biopharma, Janssen, Kyowa Kirin, GSK, Nippon Kayaku, and MedPeer. K.N. reports grants to institution from IQVIA Services Japan, Syneos Health, EPS, Nippon Kayaku, Takeda Pharmaceutical, MSD, Amgen, Taiho Pharmaceutical, Bristol Myers Squibb, Janssen, CMIC, Pfizer R&D Japan, Labcorp Laboratories Japan, Kobayashi Pharmaceutical, Pfizer Japan, Abbvie, Japan Clinical Cancer Research Organization, Eisai, EP‐CRSU, Shionogi, Otsuka Pharmaceutical, GSK, Sanofi, Chugai Pharmaceutical, Nippon Boehringer Ingelheim, SRL Medisearch, PRA Health Sciences, Astellas Pharma, Ascent Development Services, Eisai, Bayer Yakuhin, AstraZeneca, A2 Healthcare, and Thoracic Oncology Research Group; consulting fees from Ono Pharmaceutical and Eli Lilly Japan; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Ono Pharmaceutical, Daiichi Sankyo, AstraZeneca, Chugai Pharmaceutical, Eli Lilly Japan, MSD, Pfizer Japan, Nippon Boehringer Ingelheim, Incyte Biosciences Japan, Otsuka Pharmaceutical Factory, Hisamitsu Pharmaceutical, Patientricity MedPartners, Merck Biopharma, Bayer Yakuhin, Novartis, Bristol Myers Squibb, Janssen, Taiho Pharmaceutical, Medical Mobile Communications, YODOSHA, M3, Global Health Consulting Japan, The Yomiuri Shimbun, and 3H Medi Solution. T.K. reports to grants to institution from MSD, SUMMIT, Daiichi Sankyo, BeOne, Regeneron, Amgen, and Janssen; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from MSD, Ono Pharmaceutical, Chugai Pharmaceutical, Janssen, AstraZeneca, and Bristol Myers Squibb. H.H. and H.D. have no conflicts of interest to disclose.

Supporting information

Data S1: Inclusion/exclusion criteria.

Data S2: Criteria for administration.

Figure S1: Kaplan–Meier survival curves showing progression‐free survival (A) and overall survival (B) in patients eligible/ineligible for anti‐angiogenic therapies.

Figure S2: Kaplan–Meier survival curves showing progression‐free survival (A) and overall survival (B) in patients eligible/ineligible for anti‐angiogenic therapies in PBC + ICIs patients.

Figure S3: Kaplan–Meier survival curves showing progression‐free survival (A) and overall survival (B) in ICI + PBC and CRT + ICI groups.

Table S1: Treatment course.

Table S2: Dose intensity.

Table S3: Post‐anticancer treatment.

Table S4: Relationship between ORR and patient characteristics.

Table S5: Regression analysis model of relationship between PFI and PFS.

Table S6: Regression analysis model of relationship between PFI and OS.

Table S7: All AEs ≥ 20% (anti‐angiogenic therapies‐eligible/ineligible).

Table S8: All TEAEs ≥ 20% (prior regimen type CRT followed by ICI/PBC with ICI).

Data Availability Statement

The anonymized data obtained and analyzed in this study are available upon reasonable request.