Perioperative Nivolumab in Resectable Non‐Small Cell Lung Cancer: A Subanalysis of Japanese Patients From CheckMate 77T

ABSTRACT

In the randomized phase III CheckMate 77T study, perioperative nivolumab showed statistically significant and clinically meaningful improvement in event‐free survival (EFS) vs. placebo in patients with resectable, non‐metastatic non‐small cell lung cancer (NSCLC). Here, we report efficacy and safety outcomes in the Japanese subpopulation. Adults with resectable stage IIA–IIIB NSCLC were randomized 1:1 to neoadjuvant nivolumab plus chemotherapy or chemotherapy plus placebo every 3 weeks for ≤ 4 cycles, followed by surgery and adjuvant nivolumab or placebo every 4 weeks for ≤ 13 cycles. Assessments included EFS (primary endpoint), pathological complete response (pCR), major pathological response (MPR), and safety. A total of 68 Japanese patients were randomized to perioperative nivolumab (n = 40) or placebo (n = 28). At 24.9 months' median follow‐up, median EFS was not reached (NR; 95% CI: 21.4–NR) with perioperative nivolumab vs. 12.1 (95% CI: 8.1–NR) months with placebo (hazard ratio, 0.46 [95% CI: 0.22–0.95]); 18‐month EFS rates were 76.6% vs. 42.9%, respectively. The pCR rate (95% CI) was 42.5% (27.0%–59.1%) with perioperative nivolumab vs. 0% (0%–12.3%) with placebo (odds ratio [OR], not available); MPR rate (95% CI) was 52.5% (36.1%–68.5%) vs. 7.1% (0.9%–23.5%), respectively (OR, 14.37; 95% CI: 3.00–68.82). Grade 3–4 treatment‐related and surgery‐related adverse events with perioperative nivolumab vs. placebo occurred in 55.0% vs. 39.3% and 16.7% vs. 19.2% of patients. Consistent with the global population, perioperative nivolumab improved EFS, pCR, and MPR vs. placebo in the Japanese subpopulation, with no new safety signals reported, supporting its use in Japanese patients with resectable NSCLC.

Trial Registration: ClinicalTrials.gov identifier, NCT04025879

Abbreviations

AE

adverse event

AJCC

American Joint Committee on Cancer

BICR

blinded independent central review

BIPR

blinded independent pathological review

CI

confidence interval

ECOG PS

Eastern Cooperative Oncology Group performance status

EFS

event‐free survival

HR

hazard ratio

MPR

major pathological response

NA

not available

NR

not reached

NSCLC

non‐small cell lung cancer

OR

odds ratio

ORR

objective response rate

pCR

pathological complete response

PD‐1

programmed death 1

PD‐L1

programmed death ligand 1

RECIST

Response Evaluation Criteria in Solid Tumors

SAE

serious adverse event

TRAE

treatment‐related adverse event

1. Introduction

Lung cancer is the leading cause of cancer‐related mortality worldwide [1], with non‐small cell lung cancer (NSCLC) representing about 80%–85% of all cases [2]. Although curative surgery remains the standard of care for patients with early‐stage resectable NSCLC [3, 4], disease recurrence occurs in about 25%–70% of patients despite complete resection [2]. The estimated 5‐year survival rates range from 73% for stage IB disease to 41% for stage IIIA disease per the pathological staging criteria of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 8th edition [5]. In Japan, the 5‐year survival rates by pathological disease stage were similar, ranging from 65% for stage IB disease to 43% for stage IIIA disease per the 8th edition of the AJCC Cancer Staging Manual [6].

Immunotherapy, both in neoadjuvant and adjuvant settings, is emerging as an effective treatment option for resectable NSCLC. Recent studies have shown the synergistic effect of immunotherapy added to neoadjuvant chemotherapy in resectable NSCLC [7, 8]. Nivolumab, a fully human anti‐programmed death 1 (PD‐1) immune checkpoint inhibitor, in combination with platinum‐doublet chemotherapy, is now a standard neoadjuvant treatment for eligible patients with resectable NSCLC. In the phase III CheckMate 816 study, neoadjuvant nivolumab plus chemotherapy vs. chemotherapy alone demonstrated statistically significant and clinically meaningful improvements in event‐free survival (EFS) and pathological complete response (pCR) in patients with resectable NSCLC [8]. Based on the results from this study, nivolumab plus chemotherapy is approved in the United States, Japan, and other countries as a neoadjuvant therapy for eligible patients with resectable NSCLC [9, 10, 11]. In a subanalysis of CheckMate 816 in Japanese patients, neoadjuvant nivolumab plus chemotherapy resulted in longer EFS and a higher pCR rate vs. chemotherapy alone, consistent with findings in the global population [12]. In the adjuvant setting, immunotherapy has also demonstrated clinical benefit vs. best supportive care or placebo for early‐stage resectable NSCLC [13, 14].

Immunotherapy‐based perioperative regimens (i.e., neoadjuvant immunotherapy followed by surgery and adjuvant immunotherapy) could potentially combine the benefits of neoadjuvant and adjuvant immunotherapy. Perioperative immunotherapy may reduce the risk of disease progression/recurrence and improve clinical outcomes by activating systemic antitumor immune responses, thus potentially resulting in enhanced detection and eradication of micro‐metastatic disease, both before and after surgery [15, 16, 17]. In the phase II NADIM II trial, perioperative treatment with nivolumab plus chemotherapy resulted in significantly improved pCR and survival outcomes vs. chemotherapy alone in patients with stage IIIA or IIIB resectable NSCLC (per AJCC, 8th edition) [18].

The global, phase III, randomized, double‐blind CheckMate 77T trial (NCT04025879) evaluated neoadjuvant nivolumab plus chemotherapy followed by adjuvant nivolumab (i.e., perioperative nivolumab) vs. neoadjuvant placebo plus chemotherapy followed by adjuvant placebo (i.e., placebo) in patients with resectable NSCLC [19]. Results from a prespecified interim analysis (median follow‐up, 25.4 months) showed significant EFS improvement with perioperative nivolumab vs. placebo, with 18‐month EFS rates of 70.2% vs. 50.0% (hazard ratio [HR] for disease progression or recurrence, abandoned surgery, or death 0.58; 97.36% confidence interval [CI] 0.42–0.81; p < 0.001); pCR rates were 25.3% in the nivolumab group and 4.7% in the placebo group (odds ratio [OR] 6.64; 95% CI: 3.40–12.97). Based on the results of the CheckMate 77T study, perioperative nivolumab has recently been approved in the United States for the treatment of adult patients with resectable (tumors ≥ 4 cm or node positive) NSCLC and no known EGFR mutations or ALK rearrangements [20]. Several other phase III clinical trials have also shown significant EFS and pCR benefit with perioperative immunotherapy in patients with stage II–IIIB (N2 node stage) NSCLC (per AJCC, 8th edition) [21, 22, 23].

Factors including genetic characteristics, differences in healthcare systems, and inherent epidemiological and demographic differences between patients with NSCLC could impact the course of disease and lead to differences in treatment outcomes between Asian and non‐Asian populations [24]. Therefore, it is important to evaluate clinical outcomes in Japanese patients to better guide treatment decisions.

Here, we present the efficacy and safety results of perioperative nivolumab vs. placebo in Japanese patients from CheckMate 77T.

2. Materials and Methods

2.1. Patients

The study design and eligibility criteria for CheckMate 77T have been previously described [19]. Briefly, eligible patients were adults with resectable stage IIA (> 4 cm) to IIIB (N2 node stage, single‐ or multistation) NSCLC (per the AJCC Cancer Staging Manual, 8th edition) and Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1. Patients with epidermal growth factor receptor mutations or known anaplastic lymphoma kinase translocations and those who had received prior systemic anticancer treatment were excluded. This subanalysis included patients enrolled at 15 treatment centers in Japan.

The trial was approved by the institutional review board or independent ethics committee at each center and was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. Informed consent was obtained from all patients. The trial protocol has been published previously [19].

2.2. Study Design and Treatment

Patients were randomly assigned in a 1:1 ratio to receive perioperative nivolumab or placebo. In the neoadjuvant phase, patients received either nivolumab 360 mg plus platinum‐doublet chemotherapy or placebo plus platinum‐doublet chemotherapy every 3 weeks for up to four cycles. Patients with squamous tumor histology received either cisplatin plus docetaxel or carboplatin plus paclitaxel. Patients with non‐squamous tumor histology received either cisplatin plus pemetrexed, carboplatin plus pemetrexed, or carboplatin plus paclitaxel. Within 6 weeks of the last neoadjuvant treatment dose and subsequent radiologic staging, patients underwent definitive surgery (defined as completed surgery with curative intent). Abandoned surgery was defined as definitive surgery that was attempted but then halted due to an unresectable tumor or worsening of disease. During the adjuvant phase (which was initiated within 90 days of definitive surgery), patients received either nivolumab 480 mg or placebo every 4 weeks for up to 13 cycles (~1 year).

Stratification factors included baseline disease stage (II or III), tumor histology (squamous or non‐squamous), and tumor programmed death ligand 1 (PD‐L1) expression (≥ 1%, < 1%, or indeterminate/not evaluable), which was determined using the PD‐L1 immunohistochemistry 28–8 pharmDx assay (Dako, Santa Clara, CA, USA) [25].

2.3. Endpoints and Assessments

The primary and secondary endpoints of the CheckMate 77T study have been reported previously [19]. The primary endpoint was EFS, defined as the time from randomization to any one of the following events: Any disease progression precluding surgery, abandoned surgery (surgery abandoned for reasons other than unresectability or disease worsening was not classified as an EFS event), progression or recurrence with or without surgery, or death due to any cause. Disease progression was assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Patients who received subsequent therapy prior to EFS were censored at the last evaluable tumor assessment on or before the date of subsequent therapy initiation.

The following assessments were conducted in this exploratory subanalysis of Japanese patients: EFS per BICR in all randomized patients and in subgroups by baseline disease stage, tumor PD‐L1 expression, and histology type; pCR (defined as no residual viable tumor cells post surgery in the primary tumor and sampled lymph nodes) per blinded independent pathological review (BIPR); major pathological response (MPR; defined as ≤ 10% residual viable tumor cells post surgery in the primary tumor and sampled lymph nodes) per BIPR; objective response rate (ORR; defined as a complete or partial response per RECIST v1.1 prior to definitive surgery or at first scheduled tumor assessment in patients without surgery) per BICR; and safety.

2.4. Statistical Analyses

Efficacy and safety data analyses of perioperative nivolumab vs. placebo in Japanese patients were exploratory and summarized using descriptive statistics. Efficacy analyses were conducted in all randomized Japanese patients. EFS was estimated using the Kaplan–Meier method; HRs and corresponding 95% CIs were estimated using an unstratified Cox proportional hazards model. EFS rates at fixed time points were derived from Kaplan–Meier estimates, along with their corresponding two‐sided 95% log–log transformed CIs. The Newcombe method was used to calculate two‐sided 95% CIs for unweighted differences in the incidence of pCR and MPR (with 95% CIs calculated using the Clopper–Pearson method) between treatment groups. ORR and the corresponding 95% CIs were calculated using the Clopper–Pearson method.

Safety analyses included all patients who received at least one dose of any study drug in the neoadjuvant or adjuvant setting. The following safety outcomes were reported: Any‐cause adverse events (AEs), treatment‐related AEs (TRAEs), and serious AEs (SAEs), all reported between the first study treatment and 30 days after the last study treatment, including definitive surgery and radiotherapy; surgery‐related AEs reported within 90 days after definitive surgery; and treatment‐related deaths. All AEs were categorized according to the Medical Dictionary for Regulatory Activities, v26.0, and graded according to the Common Terminology Criteria for Adverse Events of the National Cancer Institute, v4.0.

3. Results

3.1. Patients and Treatment Summary

This subanalysis is based on a prespecified interim analysis (database lock: September 6, 2023). The median follow‐up was 24.9 (range, 17.8–35.4) months for Japanese patients. Overall, 68 Japanese patients were randomized to the perioperative nivolumab group (n = 40) or the placebo group (n = 28) (Figure S1). Baseline characteristics were generally balanced across treatment groups (Table 1). However, a higher proportion of patients in the perioperative nivolumab vs. placebo groups had an ECOG PS of 1 (20.0% vs. 10.7%), squamous histology (52.5% vs. 35.7%), a history of smoking (97.5% vs. 82.1%), N2 node stage (45.0% vs. 35.7%), and tumor PD‐L1 expression < 1% (40.0% vs. 28.6%).

TABLE 1.

Baseline characteristics of Japanese patients.

Characteristic	Perioperative nivolumab (n = 40)	Placebo (n = 28)
Age, median (range), years	66.5 (50.0–78.0)	67.5 (48.0–76.0)
Male, n (%)	37 (92.5)	22 (78.6)
ECOG PS, n (%)
0	32 (80.0)	25 (89.3)
1	8 (20.0)	3 (10.7)
Disease stage, n (%)
IIA–B	15 (37.5)	10 (35.7)
IIIA–B	25 (62.5)	18 (64.3)
Node stage, n (%)
N0	8 (20.0)	8 (28.6)
N1	14 (35.0)	10 (35.7)
N2 a	18 (45.0)	10 (35.7)
Single‐station	10 (25.0)	5 (17.9)
Multistation	7 (17.5)	5 (17.9)
Histology, n (%)
Squamous	21 (52.5)	10 (35.7)
Non‐squamous	19 (47.5)	18 (64.3)
Smoking status, n (%)
Current/former	39 (97.5)	23 (82.1)
Never	1 (2.5)	5 (17.9)
Tumor PD‐L1 expression b n (%)
< 1%	16 (40.0)	8 (28.6)
≥ 1%	22 (55.0)	17 (60.7)
1%–49%	14 (35.0)	10 (35.7)
≥ 50%	8 (20.0)	7 (25.0)
Not evaluable	2 (5.0)	3 (10.7)
Platinum therapy type a n (%)
Cisplatin	13	10
Carboplatin	26	18

Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; IHC, immunohistochemistry; N, node; PD‐L1, programmed death ligand 1.

^a Not reported in 1 patient in the perioperative nivolumab group.

^b Determined using the PD‐L1 IHC 28‐8 pharmDx assay (Dako).

At the time of analysis, all Japanese patients were off treatment (Figure 1). All patients in both treatment groups received neoadjuvant treatment, with 26 (65.0%) patients in the perioperative nivolumab group and 23 (82.1%) in the placebo group completing all four cycles of neoadjuvant treatment. In both treatment groups, the primary reason for neoadjuvant treatment discontinuation was study drug toxicity (perioperative nivolumab, n = 13; placebo, n = 3). Data on neoadjuvant treatment exposure are summarized in Table S1.

FIGURE 1.

Treatment and surgery summary in Japanese patients. The denominators for percentages were based on the number of patients randomized to each treatment group. AE, adverse event. ^aIncluded patient request and AEs unrelated to study treatment. ^bSurgery was abandoned in one patient in the perioperative nivolumab group. ^cone patient in the perioperative nivolumab group did not receive definitive surgery but received adjuvant treatment.

Among patients who received neoadjuvant treatment, 36 (90.0%) patients in the perioperative nivolumab group and 26 (92.9%) patients in the placebo group underwent definitive surgery (Table S2). The majority of patients underwent single lobectomy in both the perioperative nivolumab (n = 25; 69.4%) and placebo (n = 19; 73.1%) groups; bi‐lobectomy was performed in 7 (19.4%) patients in the perioperative nivolumab group and 4 (15.4%) patients in the placebo group, and pneumonectomy was performed in 1 (2.8%) and 2 (7.7%) patients, respectively. Complete (R0) resection (i.e., no residual tumor cells visible on the margin) was achieved in 34 (94.4%) and 24 (92.3%) patients in the perioperative nivolumab and placebo groups, respectively; no incomplete (R2) resections (i.e., macroscopic residual tumor) were reported. Definitive surgery was canceled in 3 (7.5%) patients in the perioperative nivolumab group and 2 (7.1%) patients in the placebo group, and abandoned in 1 (2.5%) patient in the perioperative nivolumab group. Other surgical outcomes, including reasons for canceled or delayed surgery and duration of surgery, are summarized in Table S2.

Adjuvant treatment was received by 24 (60.0%) patients in the perioperative nivolumab group and 20 (71.4%) patients in the placebo group; 18 (45.0%) and 10 (35.7%) patients completed adjuvant treatment, respectively (Figure 1), with a median (range) dose of 13 (4–13) in the perioperative nivolumab group and 11 (3–13) in the placebo group. In both treatment groups, the primary reason for discontinuation of adjuvant treatment was disease progression (perioperative nivolumab, n = 3; placebo, n = 9).

Among all randomized Japanese patients, any subsequent anticancer therapy was received by 6 (15.0%) patients in the perioperative nivolumab group and 15 (53.6%) patients in the placebo group (Table S3). Subsequent systemic therapy was received by 5 (12.5%) and 14 (50.0%) patients, respectively.

3.2. Efficacy

Among all randomized Japanese patients, median EFS per BICR with perioperative nivolumab was not reached (NR; 95% CI: 21.4–NR) vs. 12.1 (95% CI: 8.1–NR) months with placebo (HR, 0.46; 95% CI: 0.22–0.95) (Figure 2); 18‐month EFS rates were 76.6% vs. 42.9%, respectively. EFS results by baseline disease stage, tumor PD‐L1 expression, and histology type are summarized in Table S4.

FIGURE 2.

EFS per BICR in Japanese patients. BICR, blinded independent central review; CI, confidence interval; EFS, event‐free survival; HR, hazard ratio; mo, months; NR, not reached. 95% CIs for perioperative nivolumab and placebo, respectively: ^a66%–91% and 31%–67%; ^b60%–87% and 25%–60%.

The pCR rate was 42.5% (95% CI: 27.0%–59.1%) with perioperative nivolumab vs. 0% (95% CI: 0%–12.3%) with placebo (OR, not available) (Figure 3A). The MPR rate was also higher with perioperative nivolumab (52.5% [95% CI: 36.1%–68.5%]) vs. placebo (7.1% [95% CI: 0.9%–23.5%]) (OR, 14.37 [95% CI: 3.00–68.82]) (Figure 3B). ORR per BICR was 70.0% (95% CI: 53.5%–83.4%) with perioperative nivolumab vs. 35.7% (95% CI: 18.6%–55.9%) with placebo (OR, 4.20 [95% CI: 1.50–11.73]) (Table S5).

FIGURE 3.

(A) pCR and (B) MPR per BIPR in Japanese patients. BIPR, blinded independent pathological review; CI, confidence interval; MPR, major pathological response; NA, not available; OR, odds ratio; pCR, pathological complete response.

EFS appeared to be longer in patients with pCR than in those without pCR in the perioperative nivolumab group. Among patients with pCR, median EFS was NR in the perioperative nivolumab group; however, there were no patients with pCR in the placebo group. Among patients without pCR, median (95% CI) EFS was 21.3 (11.1–NR) months in the perioperative nivolumab group and 12.1 (8.1–NR) months in the placebo group (HR 0.87 [95% CI: 0.42–1.81]) (Figure S2).

3.3. Safety and Surgical Complications

Among treated patients, any‐cause AEs occurred in all 40 (100%) patients in the perioperative nivolumab group and 27 (96.4%) patients in the placebo group (Table 2). Any‐grade SAEs were reported in 21 (52.5%) and 10 (35.7%) patients, respectively. Any‐grade TRAEs occurred in 40 (100%) patients in the perioperative nivolumab group and 27 (96.4%) patients in the placebo group. The incidence of grade 3–4 TRAEs was numerically higher with perioperative nivolumab (n = 22; 55.0%) vs. placebo (n = 11; 39.3%). The most common (≥ 10%) grade 3–4 TRAEs reported were decreased neutrophil count (27.5%), decreased white blood cell count (20.0%), and febrile neutropenia (10.0%) in the perioperative nivolumab group and decreased neutrophil count (14.3%) and neutropenia (10.7%) in the placebo group (Table S6). Any‐grade TRAEs leading to treatment discontinuation were reported in 37.5% of patients in the perioperative nivolumab group and 17.9% of patients in the placebo group; grade 3–4 TRAEs leading to treatment discontinuation occurred in 20.0% and 10.7% of patients, respectively. Compared with the incidence of TRAEs overall, the incidence of TRAEs was generally similar during the neoadjuvant period and was lower during the adjuvant period in both treatment groups (Table 2).

TABLE 2.

Summary of AEs (overall, neoadjuvant, and adjuvant) in Japanese patients.

Event	Overall				Neoadjuvant period				Adjuvant period
	Perioperative nivolumab (n = 40)		Placebo (n = 28)		Perioperative nivolumab (n = 40)		Placebo (n = 28)		Perioperative nivolumab (n = 24)		Placebo (n = 20)
	Any grade	Grade 3–4	Any grade	Grade 3–4	Any grade	Grade 3–4	Any grade	Grade 3–4	Any grade	Grade 3–4	Any grade	Grade 3–4
AE of any cause, n (%)
Any	40 (100)	24 (60.0)	27 (96.4)	15 (53.6)	40 (100)	19 (47.5)	27 (96.4)	11 (39.3)	20 (83.3)	5 (20.8)	11 (55.0)	2 (10.0)
Leading to treatment discontinuation	19 (47.5)	11 (27.5)	5 (17.9)	3 (10.7)	14 (35.0)	8 (20.0)	3 (10.7)	2 (7.1)	2 (8.3)	0	1 (5.0)	0
Serious	21 (52.5)	16 (40.0)	10 (35.7)	7 (25.0)	16 (40.0)	11 (27.5)	3 (10.7)	2 (7.1)	3 (12.5)	2 (8.3)	3 (15.0)	2 (10.0)
TRAE, n (%)
Any	40 (100)	22 (55.0)	27 (96.4)	11 (39.3)	40 (100)	19 (47.5)	27 (96.4)	11 (39.3)	14 (58.3)	3 (12.5)	3 (15.0)	0
Leading to treatment discontinuation	15 (37.5)	8 (20.0)	5 (17.9)	3 (10.7)	13 (32.5)	7 (17.5)	3 (10.7)	2 (7.1)	1 (4.2)	0	1 (5.0)	0
Serious	17 (42.5)	12 (30.0)	3 (10.7)	2 (7.1)	14 (35.0)	10 (25.0)	3 (10.7)	2 (7.1)	3 (12.5)	2 (8.3)	0	0
Death	1 (2.5) a	0	0	0	0	0	0	0	0	0	0	0
Surgery‐related AE, n/N b (%)	19 (52.8)	6 (16.7)	12 (46.2)	5 (19.2)	0	0	0	0	0	0	0	0

Abbreviations: AE, adverse event; TRAE, treatment‐related adverse event.

^a Patient had completed neoadjuvant therapy, but definitive surgery was canceled due to grade 3 colitis and patient did not receive any adjuvant therapy; death due to grade 4 pneumonitis occurred 155 days since the last dose of nivolumab.

^b The denominator represents the number of patients who had undergone definitive surgery (n = 36 in the perioperative nivolumab group, n = 26 in the placebo group). Events reported within 90 days after definitive surgery were included.

One treatment‐related death due to grade 4 pneumonitis was reported in the perioperative nivolumab group (Table 2). The patient was a 63‐year‐old male with a medical history of chronic obstructive pulmonary disease, sinus tachycardia, gout, both inguinal hernias, and hives. Key prior/concomitant medications included allopurinol, amlodipine besylate, fluticasone propionate, formoterol fumarate, furosemide, oxycodone hydrochloride, and olanzapine. Definitive surgery was canceled for this patient due to the occurrence of grade 3 colitis after completion of neoadjuvant therapy, and no adjuvant therapy was administered. Grade 3 pneumonitis was reported on day 131 after the last infusion of nivolumab, which worsened to grade 4 on day 132. The patient died 155 days after the last dose of nivolumab.

Among patients who underwent definitive surgery, any‐grade surgery‐related AEs were reported in 52.8% of patients in the perioperative nivolumab group and 46.2% in the placebo group, with 16.7% and 19.2% of patients, respectively, experiencing grade 3–4 events (Table 2). The most common (≥ 8%) any‐grade surgery‐related AEs reported were procedural pain (11.1%) and constipation (8.3%) with perioperative nivolumab and atrial fibrillation (11.5%) with placebo (Table S7). The most commonly occurring (≥ 5%) grade 3–4 surgery‐related AEs were pulmonary fistula (5.6%) with perioperative nivolumab and atelectasis (7.7%) with placebo (Table S7). Grade 5 surgery‐related AEs (defined as AEs that result in death ≤ 24 h after onset) were not reported in either treatment group. In the perioperative nivolumab group, definitive surgery was delayed in one patient due to Guillain‐Barré syndrome and canceled in one patient due to grade 3–4 colitis. No AEs leading to delay or cancellation of definitive surgery were reported in the placebo group (Table S7).

4. Discussion

In the Japanese subpopulation of CheckMate 77T, perioperative nivolumab demonstrated improvement in EFS vs. placebo (HR, 0.46; 95% CI: 0.22–0.95) and was associated with a higher proportion of patients with pCR (42.5% vs. 0%) and MPR (52.5% vs. 7.1%), consistent with the results in the global population [19]. Although cross–trial comparisons should be made with caution owing to differences in study design, patient populations, and sample sizes, the results of this subanalysis are consistent with findings from previous studies, which have shown clinical benefit with perioperative immunotherapy in Asian or Japanese patients with resectable NSCLC [23, 26].

Greater clinical benefit with respect to pathological response was observed with perioperative nivolumab vs. placebo in Japanese patients, consistent with findings in the global population [19]. The rates of pCR and MPR were numerically higher in the perioperative nivolumab group in the Japanese subpopulation vs. those in the global population (pCR: 42.5% vs. 25.3%; MPR: 52.5% vs. 35.4%, respectively) [19]. Numerically higher rates of pCR and MPR with neoadjuvant nivolumab plus chemotherapy were also observed in the Japanese subpopulation vs. the global population of CheckMate 816 [8, 12]. Recent studies have suggested pathological response to neoadjuvant therapy as a potential surrogate endpoint for survival outcomes in resectable NSCLC [27, 28, 29]. Results from the global population of CheckMate 77T showed that EFS favored perioperative nivolumab over placebo both in patients with pCR and in those without pCR, which was consistent with the results for neoadjuvant nivolumab plus chemotherapy in CheckMate 816 and with findings from other clinical trials evaluating perioperative immunotherapy [8, 18, 19, 22, 30]. A similar trend was observed with perioperative nivolumab in this subanalysis of Japanese patients. However, definitive conclusions are limited by the small sample size of the Japanese subpopulation. Further research is warranted to investigate the association of pCR with survival outcomes in Japanese patients with resectable NSCLC.

Surgical outcomes were generally similar in the two treatment groups in this subanalysis, suggesting that neoadjuvant nivolumab plus chemotherapy did not negatively impact surgical outcomes in Japanese patients. These findings are consistent with those for the global population and with the results for neoadjuvant nivolumab plus chemotherapy in CheckMate 816 [8, 19].

No new safety signals were reported in this subanalysis of Japanese patients, and safety outcomes were generally consistent with those of the global population. Compared with the global population [19], the rates of grade 3–4 TRAEs and TRAEs leading to treatment discontinuation were numerically higher in both treatment groups in Japanese patients. However, it should be noted that the safety outcomes observed in this analysis were similar to those previously reported in the CheckMate 816 subanalysis in Japanese patients [12]. Studies have shown that genetic characteristics, differences in healthcare systems, and epidemiological and demographic differences between Asian and non‐Asian populations may influence the response to treatments for NSCLC [24], which could possibly explain the differences in safety outcomes between Japanese patients and the global population. AEs were more commonly reported during the neoadjuvant period compared with the adjuvant period in both treatment groups among the Japanese patients in this study, similar to those reported for the global population [19]. However, given that one treatment‐related death in the perioperative nivolumab group due to grade 4 pneumonitis occurred 155 days after the last dose of neoadjuvant nivolumab, long‐term careful monitoring is needed even after the completion of nivolumab treatment.

This exploratory subanalysis was not statistically powered to test for differences between treatment groups. Furthermore, data interpretation and generalization were limited by small sample sizes. Long‐term survival data are needed to confirm the clinical benefit of perioperative nivolumab for resectable NSCLC in the Japanese subpopulation.

In conclusion, perioperative nivolumab vs. placebo improved EFS, with higher rates of pCR and MPR observed in Japanese patients from CheckMate 77T. No unexpected safety signals were reported with this treatment regimen. Consistent with findings in the global population, these data support the use of perioperative nivolumab as an effective treatment option for patients with resectable NSCLC, including Japanese patients.

Author Contributions

Fumihiro Tanaka: conceptualization, investigation, writing – review and editing. Yasutaka Watanabe: conceptualization, investigation, writing – review and editing. Shunichi Sugawara: investigation, writing – review and editing. Jiro Okami: investigation, writing – review and editing. Satoshi Muto: investigation, writing – review and editing. Morihito Okada: investigation, writing – review and editing. Yoshitsugu Horio: investigation, writing – review and editing. Masahiro Tsuboi: investigation, writing – review and editing. Yuki Sato: investigation, writing – review and editing. Kazuya Takamochi: investigation, writing – review and editing. Hidehito Horinouchi: investigation, writing – review and editing. Yuichi Tambo: investigation, writing – review and editing. Masahiro Seike: investigation, writing – review and editing. Kyoichi Okishio: investigation, writing – review and editing. Cinthya Coronado Erdmann: conceptualization, data curation, formal analysis, writing – review and editing. Padma Sathyanarayana: conceptualization, data curation, formal analysis, writing – review and editing. Stephanie Meadows‐Shropshire: conceptualization, data curation, formal analysis, writing – review and editing. Hiroyuki Ito: investigation, writing – review and editing.

Funding

This work was supported by Bristol Myers Squibb.

Ethics Statement

The trial was approved by the institutional review board or independent ethics committee at each center and was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.

Consent

Informed consent was obtained from all patients.

Conflicts of Interest

C.C.E. reports financial interests, personal, full or part‐time employment from BMS; financial interests, personal, stocks, or ownership from BMS. F.T. reports financial interests, personal and institutional, research grant from Boehringer Ingelheim Japan, Chugai Pharmaceutical, Eli Lilly Japan, Ono Pharmaceutical, Taiho Pharmaceutical; financial interests, personal, speaker, consultant, advisor from AstraZeneca, Chugai Pharmaceutical, Ono Pharmaceutical; financial interests, personal, speaker's bureau from AstraZeneca, BMS, Boehringer Ingelheim Japan, Chugai Pharmaceutical, Covidien Japan, Eli Lilly Japan, Intuitive Japan, Johnson and Johnson, Kyowa Kirin, MSD, Olympus, Ono Pharmaceutical, Pfizer, Stryker, Taiho Pharmaceutical, and Takeda Pharmaceutical. H.H. reports research grants from AbbVie, AstraZeneca, BMS, Chugai Pharmaceutical, Daiichi Sankyo, Janssen, MSD, Ono, and Roche; honoraria from AbbVie, Amgen, AstraZeneca, BMS, Chugai Pharmaceutical, Eli Lilly, MSD, Ono, and Roche; and Advisory board for AbbVie, AstraZeneca, BMS, Chugai, Ono, and Roche. H.I. reports financial interests, personal, speaker's bureau from BMS, Johnson and Johnson, and Ono Pharmaceutical. J.O. reports honoraria from AstraZeneca, BMS, Chugai Pharmaceutical, and Ono Pharmaceutical; stocks from Takeda Pharmaceutical. K.O. reports honoraria from AstraZeneca K.K., BMS K.K., Chugai Pharmaceutical, Nippon Kayaku, Sawai Pharmaceutical, Taiho Pharmaceutical, and Takeda Pharmaceutical. K.T. reports honoraria from AstraZeneca, Chugai Pharmaceutical, Eli Lilly, Johnson and Johnson, Medtronic, and Ono Pharmaceutical. M.S. reports research grants from Chugai Pharmaceutical, Eli Lilly, Kyowa Hakko Kirin, Nippon Kayaku, and Taiho Pharmaceutical; honoraria from Amgen, AstraZeneca, BMS, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Kyowa Hakko Kirin, Merck Biopharma, MSD K.K., Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, and Takeda Pharmaceutical. M.T. reports research grant, commissioned research (e.g., clinical trials) from AstraZeneca K.K., BMS K.K., Eli Lilly Japan, MiRXES, MSD, Novartis, and Ono Pharmaceutical Co Ltd.; honorarium, lecture fee from Amgen K.K., AstraZeneca K.K., BMS K.K., Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Johnson and Johnson Japan, Medtronic Japan, MSD, Novartis, Ono Pharmaceutical, and Taiho Pharmaceutical; consulting or advisory role for AstraZeneca K.K., Chugai Pharmaceutical, MSD, and Novartis. P.S. reports financial interests, personal, full or part‐time employment from BMS; financial interests, personal, stocks, or ownership from BMS. S.M. reports financial interests, institutional, research grant from AstraZeneca K.K., BMS K.K., Chugai Pharmaceutical, FIMECS Inc.; financial interests, personal, speaker from Chugai Pharmaceutical. S.M.‐S. reports financial interests, personal, full or part‐time employment from BMS; financial interests, personal, stocks, or ownership from BMS. S.S. reports financial interests, personal and institutional, contracts from A2 Healthcare, Accerise, Amgen, AnHeart Therapeutics, AstraZeneca, BMS, Chugai Pharmaceutical, Daiichi Sankyo, MSD, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda Pharmaceutical, and Parexel International. Y.H. reports personal and institutional research funding from AbbVie, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, MSD, Novartis, Ono Pharmaceutical, Taiho Pharmaceutical, and Takeda Pharmaceutical. Y.S. reports honoraria from AstraZeneca, BMS, Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Kyowa Kirin, MSD, Nippon Kayaku, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, and Takeda Pharmaceutical. Y.T. reports honoraria from AstraZeneca, BMS, Chugai, Daiichi Sankyo, Kyowa Kirin, MSD, Pfizer, Taiho, Takeda Pharmaceutical; research funding from AstraZeneca, Beigene, BMS, Daiichi Sankyo, Gilead, MSD, Ono Pharmaceutical, Regeneron. The authors M.O. and Y.W. declare no conflicts of interest.

Supporting information

TABLE S1: Neoadjuvant treatment exposure in Japanese patients.

TABLE S2: Surgical outcomes in Japanese patients.

TABLE S3: Subsequent anticancer therapy in Japanese patients.

TABLE S4: EFS per BICR by baseline disease stage, tumor PD‐L1 expression, and histology type in Japanese patients.

TABLE S5: ORR and the best overall response per BICR in Japanese patients.

TABLE S6: Summary of TRAEs (≥ 10% incidence in either treatment group) in Japanese patients.

TABLE S7: Summary of AEs leading to surgical delay/cancellation and surgery‐related AEs in Japanese patients.

FIGURE S1: Consolidated Standards of Reporting Trials (CONSORT) diagram of patient disposition.

FIGURE S2: Event‐free survival in Japanese patients with and without pCR.

Data Availability Statement

Data are available upon reasonable request. Bristol Myers Squibb policy on data sharing may be found at https://www.bms.com/researchers‐and‐partners/independent‐research/data‐sharing‐request‐process.html.