Abstract
Background
Neoadjuvant nivolumab plus chemotherapy significantly improved event-free survival (EFS) and pathologic complete response (pCR) versus chemotherapy alone in patients with resectable non-small-cell lung cancer (NSCLC) in the global phase III CheckMate 816 study. Here, we report post hoc exploratory efficacy, safety, and surgical outcomes in the Chinese subpopulation of this study.
Methods
Adults with stage IB-IIIA resectable NSCLC were randomized to receive nivolumab 360 mg plus chemotherapy or chemotherapy alone every 3 weeks for three cycles followed by surgery. Primary endpoints included EFS and pCR (both per blinded independent review). EFS and pCR results were from 14 October 2022, and 16 September 2020, database locks, respectively.
Results
The Chinese subpopulation comprised 97 patients (nivolumab plus chemotherapy, 44; chemotherapy, 53). At 38.2 months of minimum follow-up, median EFS was not reached [95% confidence interval (CI) 23.4 months-not reached] in the nivolumab plus chemotherapy arm and 13.9 months (95% CI 8.3-34.3 months) in the chemotherapy arm (hazard ratio 0.47, 95% CI 0.25-0.88). pCR rates were 25.0% (95% CI 13.2% to 40.3%) and 1.9% (95% CI 0.0% to 10.1%), respectively (odds ratio 11.05; 95% CI 1.41-86.49). Of 97 Chinese patients, 36 (82%) in the nivolumab plus chemotherapy arm and 41 (77%) in the chemotherapy arm underwent definitive surgery. Grade 3-4 treatment-related adverse events occurred in 18/43 patients (42%) treated with nivolumab plus chemotherapy and 22/53 patients (42%) treated with chemotherapy.
Conclusions
Consistent with findings in the global study population of CheckMate 816, neoadjuvant nivolumab plus chemotherapy improved EFS and pCR versus chemotherapy in the Chinese subpopulation without impacting treatment tolerability or the feasibility of surgery. These findings support the use of nivolumab plus chemotherapy as a standard neoadjuvant treatment option for Chinese patients with resectable NSCLC.
Key words: immunotherapy, immune checkpoint inhibitors, China, subgroup analysis, non-small-cell lung cancer
Highlights
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This is a post hoc CheckMate 816 analysis of neoadjuvant nivolumab + chemotherapy in Chinese patients with resectable NSCLC.
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Nivolumab + chemotherapy demonstrated clinically meaningful improvements in EFS and pCR versus chemotherapy alone.
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Neoadjuvant nivolumab + chemotherapy did not impact treatment tolerability or the feasibility of surgery.
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No new safety signals with neoadjuvant nivolumab + chemotherapy were observed in the Chinese subpopulation.
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These results support the use of neoadjuvant nivolumab + chemotherapy in Chinese patients with resectable NSCLC.
Introduction
Non-small-cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for ∼85% of all cases.1 Despite 20%-25% of patients with NSCLC having resectable disease at diagnosis,2 30%-55% of these patients experience disease recurrence after undergoing curative-intent surgery and eventually die due to NSCLC.3,4 Systemic neoadjuvant therapy can improve surgical outcomes, prevent recurrence, and ultimately enhance survival in patients with resectable NSCLC, but treatment options have historically been limited.5 In global populations, neoadjuvant chemotherapy only provides modest clinical benefit compared with surgery alone [up to 5% improvement in 5-year overall survival (OS)].6 The long-term efficacy of neoadjuvant chemotherapy may be further attenuated in patients from certain geographic regions, with some studies in Chinese patients reporting no significant OS benefit compared with surgery alone at 5 years of follow-up or beyond.7,8 These findings highlight the need for novel, efficacious neoadjuvant treatment options for patients with resectable NSCLC.
Nivolumab, a fully human anti-programmed cell death protein 1 (PD-1) antibody, has demonstrated substantial clinical benefit both in patients with non-metastatic and metastatic NSCLC.9, 10, 11 Nivolumab restores the antitumor activity of existing T cells by blocking interactions between PD-1 receptors and their ligands.5,12, 13, 14 In combination with chemotherapy as neoadjuvant treatment, nivolumab may enhance the immune response against tumor antigens and target micrometastatic disease.5,12, 13, 14 Earlier findings from phase II studies suggested promising clinical activity with nivolumab-based treatment regimens in patients with resectable NSCLC, as assessed by pathologic complete response (pCR) and survival outcomes.15,16 Most recently, in the pivotal open-label phase III CheckMate 816 study (NCT02998528), nivolumab plus chemotherapy demonstrated statistically significant and clinically meaningful improvements in both primary endpoints of event-free survival [EFS; hazard ratio (HR) 0.63, 97.38% confidence interval (CI) 0.43-0.91, P = 0.005] and pCR [odds ratio (OR) 13.94, 99% CI 3.49-55.75, P < 0.001] versus chemotherapy alone in patients with resectable NSCLC,9 with continued EFS benefit observed in the global study population at 3 years of follow-up (HR 0.68, 95% CI 0.49-0.93).17 Based on the primary results of CheckMate 816, nivolumab plus chemotherapy was approved in the United States and several other countries, including China, Hong Kong, Japan, Singapore, South Korea, Taiwan, and Thailand, as the first immunotherapy-based neoadjuvant treatment regimen for adults with resectable (tumors ≥4 cm and/or node-positive) NSCLC.18, 19, 20, 21, 22, 23, 24, 25 Moreover, National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®) also recommend nivolumab plus chemotherapy as a systemic neoadjuvant treatment option for patients with resectable NSCLC.26
Chinese patients account for ∼37% of all new global lung cancer cases.27,28 Subpopulation analyses from global clinical trials are needed to evaluate the clinical profile of treatment and to study the potential impact of race and ethnicity, as well as that of regional differences in clinical practices and health care systems, on treatment outcomes.29, 30, 31 Here, we report efficacy, safety, and surgical outcomes with neoadjuvant nivolumab plus chemotherapy versus chemotherapy alone in the Chinese subpopulation of patients with resectable NSCLC from CheckMate 816 at 3 years’ minimum follow-up.
Methods
Study design and patients
The study design, patient eligibility criteria, and protocol of CheckMate 816 have been previously described.9 Briefly, CheckMate 816 is an ongoing, global, open-label, randomized phase III study in treatment-naive adults with resectable stage IB (≥4 cm)-IIIA NSCLC (per American Joint Committee on Cancer 7th edition staging criteria), Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1, and no known sensitizing EGFR mutations or ALK alterations. Patients were stratified by baseline tumor programmed death-ligand 1 (PD-L1) expression (≥1% versus <1%, not evaluable, or indeterminate), disease stage (IB-II versus IIIA), and sex, and were randomized in a 1 : 1 ratio to receive either nivolumab 360 mg plus platinum-doublet chemotherapy or platinum-doublet chemotherapy alone every 3 weeks for three cycles before undergoing definitive surgery within 6 weeks of completing neoadjuvant treatment. Enrollment to the third treatment arm of the study, nivolumab plus ipilimumab, closed early after the primary analysis population of the study was modified to nivolumab plus chemotherapy versus chemotherapy based on data from external trials.15,16 Per investigator discretion following surgery, all patients could receive up to four cycles of adjuvant chemotherapy and/or radiotherapy. Dosing information for specific neoadjuvant and adjuvant chemotherapy regimens is provided in the Supplementary Appendix, available at https://doi.org/10.1016/j.esmoop.2023.102040.
CheckMate 816 was carried out in accordance with the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. The study protocol of CheckMate 816 and all amendments were approved by an institutional review board or independent ethics committee at each study site, and an independent data and safety monitoring committee monitored and reviewed the efficacy and safety of all evaluated treatments. All patients provided written informed consent before initiating study procedures.
Endpoints and assessments
The primary and secondary endpoints of CheckMate 816 have been previously reported.9 Here, we assessed efficacy, safety, and surgical outcomes in the Chinese subpopulation (i.e. patients from the 23 study centers in China and Taiwan), including: (i) EFS {time from randomization to progressive disease [PD; according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1] that precluded surgery, PD after surgery, PD in the absence of surgery, or death due to any cause} per blinded independent central review (BICR); (ii) pCR (0% residual viable tumor cells in the primary tumor and sampled lymph nodes at the time of surgery) per blinded independent pathologic review (BIPR); (iii) major pathologic response (MPR; ≤10% residual viable tumor cells in the primary tumor and sampled lymph nodes at the time of surgery) per BIPR; (iv) time to death or distant metastasis [TTDM; time from randomization to first distant metastasis (any new lesion that developed outside of the thorax according to RECIST version 1.1) or to death in the absence of distant metastasis] per BICR; (v) EFS on next-line therapy (EFS2; time from randomization to documented investigator-assessed PD after initiating next-line therapy or to death from any cause); (vi) objective response rate (ORR; according to RECIST version 1.1) per BICR; (vii) safety; and (viii) surgical outcomes (e.g. completed surgery, delayed or canceled surgery, duration of surgery, length of hospital stay following surgery, surgical approach, extent and completeness of resection). Adverse events (AEs), including immune-mediated AEs (IMAEs), treatment-related AEs (TRAEs; AEs reported between the first neoadjuvant dose and 30 days after the last neoadjuvant dose), and surgery-related AEs (AEs reported within 90 days of definitive surgery) were assessed in all treated patients and categorized according to Common Terminology Criteria for Adverse Events version 4.0 and Medical Dictionary for Regulatory Activities version 25.0. Additional information regarding AE assessments and postoperative tumor assessments is provided in the Supplementary Appendix, available at https://doi.org/10.1016/j.esmoop.2023.102040.
Statistical analysis
All analyses in the Chinese subpopulation were descriptive in nature and were not powered for statistical significance. Efficacy and surgical endpoints were evaluated in concurrently randomized patients, and safety outcomes were evaluated in patients who received one or more doses of neoadjuvant study treatment. EFS, TTDM, and EFS2 were estimated using the Kaplan–Meier method, with HRs and associated two-sided 95% CIs calculated using an unstratified Cox proportional hazards model with treatment arm as a single covariate. Point estimates for comparisons of pCR and MPR were calculated using the unstratified Cochran–Mantel–Haenszel method. ORRs and corresponding two-sided 95% CIs were calculated using the Clopper–Pearson method. pCR, MPR, and ORR were from the final pathologic response database lock (16 September 2020). All other efficacy and safety results in the Chinese subpopulation of CheckMate 816 were from the 14 October 2022, prespecified interim database lock for EFS in the global concurrently randomized population.
Results
Patients and treatment exposure
Overall, CheckMate 816 enrolled 773 patients; 505 underwent randomization, and 358 were concurrently assigned to nivolumab plus chemotherapy (n = 179) or chemotherapy alone (n = 179). Of 175 Chinese patients enrolled, 44 were randomized to nivolumab plus chemotherapy, and 53 were randomized to chemotherapy alone (Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2023.102040); 43 patients and 53 patients in the respective treatment arms received one or more doses of study drug. Baseline characteristics in the Chinese subpopulation were generally balanced between the nivolumab plus chemotherapy and chemotherapy arms, with the exception of ECOG PS 1 [8 patients (18%) versus 20 patients (38%) in the nivolumab plus chemotherapy and chemotherapy arms, respectively] and stage IIIA NSCLC [26 patients (59%) versus 39 patients (74%); Table 1].
Table 1.
Baseline characteristics in the Chinese subpopulation
| Nivolumab plus chemotherapy (n = 44) | Chemotherapy (n = 53) | |
|---|---|---|
| Age | ||
| Median (range), years | 62.0 (47.0-74.0) | 63.0 (35.0-83.0) |
| <65 years | 28 (64) | 30 (57) |
| ≥65 years | 16 (36) | 23 (43) |
| Sex | ||
| Male | 41 (93) | 47 (89) |
| Female | 3 (7) | 6 (11) |
| ECOG PS | ||
| 0 | 36 (82) | 33 (62) |
| 1 | 8 (18) | 20 (38) |
| Disease stagea | ||
| IB-II | 18 (41) | 13 (25) |
| IIIA | 26 (59) | 39 (74) |
| Tumor histology | ||
| Squamous | 33 (75) | 37 (70) |
| Non-squamous | 11 (25) | 16 (30) |
| Smoking status | ||
| Never smoked | 5 (11) | 7 (13) |
| Current or former smoker | 39 (89) | 46 (87) |
| Tumor PD-L1 expressionb | ||
| Not evaluable | 4 (9)c | 5 (9)c |
| <1% | 12 (27) | 17 (32) |
| ≥1% | 28 (64) | 31 (58) |
| 1% to 49% | 14 (32) | 15 (28) |
| ≥50% | 14 (32) | 16 (30) |
Data reported as n (%) unless otherwise indicated. Percentages may not total 100% due to rounding.
AJCC, American Joint Committee on Cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; IHC, immunohistochemistry; PD-L1, programmed death-ligand 1; TNM, tumor, node, metastasis.
Per AJCC TNM 7th edition staging criteria, as reported in case report forms; one patient (2%) in the chemo arm had stage IV disease at baseline.
Per Dako PD-L1 IHC 28-8 pharmDx assay.
Stratified to the tumor PD-L1 <1% subgroup for subgroup analyses by baseline tumor PD-L1 expression.
At database lock (14 October 2022), all patients in the Chinese subpopulation had discontinued neoadjuvant treatment. Forty patients (93%) in the nivolumab plus chemotherapy arm and 48 patients (91%) in the chemotherapy arm completed the per-protocol neoadjuvant treatment regimen (Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2023.102040). Following surgery, 14 patients (32%) and 32 patients (60%) in the nivolumab plus chemotherapy and chemotherapy arms, respectively, received adjuvant therapy (Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2023.102040); subsequent cancer therapy was administered to 11 (25%) and 33 (62%), respectively (Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2023.102040).
Surgical outcomes
Among randomized patients in the Chinese subpopulation, 36 (82%) in the nivolumab plus chemotherapy arm and 41 (77%) in the chemotherapy arm underwent definitive surgery (Table 2). Surgery was cancelled for 7 patients (16%) and 12 patients (23%) in the nivolumab plus chemotherapy and chemotherapy arms, respectively, due to disease progression (four patients and six patients, respectively) or other reasons (e.g. patient refusal, unresectability, poor lung function). Surgery was delayed for three patients (8%) and four patients (10%) in the nivolumab plus chemotherapy and chemotherapy arms, respectively, due to AEs (one patient in each treatment arm) or other reasons (two patients and three patients, respectively).
Table 2.
Summary of surgical outcomes in the Chinese subpopulation
| Nivolumab plus chemotherapy (n = 44)a | Chemotherapy (n = 53) | |
|---|---|---|
| Completed definitive surgery, n (%) | 36 (82) | 41 (77) |
| Cancelled definitive surgery, n (%) | 7 (16) | 12 (23) |
| Disease progressionb | 4 (57) | 6 (50) |
| Otherb | 3 (43) | 6 (50) |
| Delayed definitive surgery, n (%) | 3 (8) | 4 (10) |
| Adverse eventc | 1 (33) | 1 (25) |
| Otherc | 2 (67) | 3 (75) |
| Length of delay in definitive surgery | ||
| Median (IQR), weeks | 1.1 (0.1-2.6) | 1.2 (0.4-2.4) |
| ≤2 weeks, n (%)c | 2 (67) | 3 (75) |
| >2-4 weeks, n (%)c | 1 (33) | 1 (25) |
| Median duration of definitive surgery (IQR), minutes | 156.5 (123.5-201.0) | 158.0 (115.0-238.0) |
| Surgical approach, n (%)d | ||
| Minimally invasive | 11 (31) | 10 (24) |
| Thoracotomy | 23 (64) | 20 (49) |
| Minimally invasive to thoracotomy | 2 (6) | 11 (27) |
| Extent of resection, n (%)d,e | ||
| Lobectomy | 21 (58) | 20 (49) |
| Sleeve lobectomy | 2 (6) | 5 (12) |
| Bilobectomy | 0 | 1 (2) |
| Pneumonectomy | 12 (33) | 12 (29) |
| Other | 6 (17) | 6 (15) |
| Completeness of resection, n (%)d | ||
| R0 | 35 (97) | 38 (93) |
| R1 | 0 | 3 (7) |
| R2 | 0 | 0 |
| RX | 1 (3) | 0 |
| Median length of hospital stay following definitive surgery (IQR), days | 11.5 (9.0-15.0) | 11.0 (9.0-15.0) |
Percentages may not total 100% due to rounding.
IQR, interquartile range; R0, no residual tumor; R1, microscopic residual tumor; R2, macroscopic residual tumor; RX, unknown residual tumor.
The surgical status of one patient was not reported.
Denominator based on patients with cancelled surgery.
Denominator based on patients with delayed surgery.
Denominator based on patients who underwent surgery.
Patients may have undergone one or more types of surgery.
Median duration of surgery was similar between patients in the nivolumab plus chemotherapy and chemotherapy arms (156.5 and 158.0 min, respectively; Table 2). Among patients who underwent surgery, thoracotomy was the most common surgical approach in both treatment arms [nivolumab plus chemotherapy, 23 patients (64%); chemotherapy, 20 patients (49%)], followed by a minimally invasive approach [11 (31%); 10 (24%)] and conversion from a minimally invasive approach to thoracotomy [2 (6%); 11 (27%)]. With respect to extent of resection, 21 patients (58%) and 20 patients (49%) in the nivolumab plus chemotherapy and chemotherapy arms, respectively, underwent lobectomy, and 12 (33%) and 12 (29%) underwent pneumonectomy. Most patients in both treatment arms [nivolumab plus chemotherapy, 35 patients (97%); chemotherapy, 38 patients (93%)], had R0 resection (i.e. no residual tumor).
Efficacy
At 38.2 months of minimum follow-up (median, 42.4 months), nivolumab plus chemotherapy improved EFS versus chemotherapy in the Chinese subpopulation. Median EFS was not reached (NR; 95% CI 23.4 months-NR) in the nivolumab plus chemotherapy arm and 13.9 months (95% CI 8.3-34.3 months) in the chemotherapy arm (HR 0.47, 95% CI 0.25-0.88; Figure 1A); 3-year EFS rates were 59% (95% CI 41% to 73%) and 35% (95% CI 22% to 49%), respectively. EFS favored nivolumab plus chemotherapy versus chemotherapy across key subgroups defined by baseline disease stage, tumor histology, and tumor PD-L1 expression (Figure 1B).
Figure 1.
EFS in the Chinese subpopulation. (A) Kaplan–Meier curve of EFS per BICR. (B) Forest plot of EFS per BICR in key patient subgroups. Patients who received subsequent therapy were censored at the last evaluable tumor assessment on or before the date of subsequent therapy. AJCC, American Joint Committee on Cancer; BICR, blinded independent central review; chemo; chemotherapy; CI, confidence interval; EFS, event-free survival; HR, hazard ratio; NIVO, nivolumab; NR, not reached; PD-L1, programmed death-ligand 1; TNM, tumor–node–metastasis. a95% CI 41% to 73%. b95% CI 22% to 49%. cPer AJCC TNM 7th edition staging criteria, as reported in case reported forms.
In the Chinese subpopulation, nivolumab plus chemotherapy improved pathologic response versus chemotherapy. pCR rates were 25.0% (95% CI 13.2% to 40.3%) in the nivolumab plus chemotherapy arm and 1.9% (95% CI 0.0% to 10.1%) in the chemotherapy arm (OR 11.05, 95% CI 1.41-86.49; Figure 2A). Similar improvements in pCR were observed with nivolumab plus chemotherapy versus chemotherapy across most key subgroups (Supplementary Figure S2, available at https://doi.org/10.1016/j.esmoop.2023.102040). MPR rates were higher with nivolumab plus chemotherapy (34.1%, 95% CI 20.5% to 49.9%) than with chemotherapy (7.5%, 95% CI 2.1% to 18.2%; OR 7.42; 95% CI 1.92-28.65; Figure 2B). Greater depth of pathologic response was observed with nivolumab plus chemotherapy versus chemotherapy (median percent residual viable tumor cells in the primary tumor, 10% versus 68%; Supplementary Figure S3, available at https://doi.org/10.1016/j.esmoop.2023.102040). EFS appeared to be prolonged in patients who had pCR compared with those who did not: median EFS was NR in either treatment arm among patients with pCR, and 36.0 months (95% CI 11.1 months-NR) and 13.9 months (95% CI 8.3-34.3 months) with nivolumab plus chemotherapy and chemotherapy, respectively, in patients without pCR (Supplementary Figure S4, available at https://doi.org/10.1016/j.esmoop.2023.102040).
Figure 2.
Pathologic response in the Chinese subpopulation. (A) Bar graph of pCR per BIPR. (B) Bar graph of MPR per BIPR. Patients who did not undergo surgery were classified as non-responders. BIPR, blinded independent pathologic review; chemo, chemotherapy; CI, confidence interval; MPR, major pathologic response; NIVO, nivolumab; OR, odds ratio; pCR, pathologic complete response. aUnstratified analysis. b95% CI 13.2% to 40.3%. c95% CI 0.0% to 10.1%. d95% CI 20.5% to 49.9%. e95% CI 2.1% to 18.2%.
Nivolumab plus chemotherapy prolonged TTDM compared with chemotherapy in the Chinese subpopulation. Median TTDM was NR in the nivolumab plus chemotherapy arm and 28.8 months (95% CI 14.8-46.8 months) in the chemotherapy arm (Supplementary Figure S5, available at https://doi.org/10.1016/j.esmoop.2023.102040); 3-year TTDM rates were 81% (95% CI 64% to 90%) and 42% (95% CI 27% to 56%), respectively. Nivolumab plus chemotherapy also prolonged EFS2 compared with chemotherapy. Median EFS2 was NR in the nivolumab plus chemotherapy arm and 37.2 months (95% CI 17.7 months-NR) in the chemotherapy arm (Supplementary Figure S6, available at https://doi.org/10.1016/j.esmoop.2023.102040); 3-year EFS2 rates were 81% (95% CI 66% to 90%) and 51% (95% CI 37% to 63%), respectively.
Overall, 23 patients (52%) in the nivolumab plus chemotherapy arm and 22 patients (42%) in the chemotherapy arm of the Chinese subpopulation had an objective response (Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2023.102040); complete response was reported in 0 patients and 1 patient (2%), respectively. Before definitive surgery, radiographic downstaging was observed in 14 patients (32%) and 9 patients (17%) in the nivolumab plus chemotherapy and chemotherapy arms, respectively (Supplementary Table S4, available at https://doi.org/10.1016/j.esmoop.2023.102040).
Safety
As of the 14 October 2022, database lock, 42 patients (98%) treated with nivolumab plus chemotherapy and 51 patients (96%) treated with chemotherapy in the Chinese subpopulation reported any-cause AEs, including grade 3-4 AEs in 20 patients (46%) and 23 patients (43%), respectively (Table 3). Any-grade TRAEs occurred in 38 patients (88%) and 47 patients (89%) treated with nivolumab plus chemotherapy and chemotherapy, respectively; grade 3-4 TRAEs occurred in 18 patients (42%) and 22 patients (42%), respectively. In the nivolumab plus chemotherapy and chemotherapy arms, the most common any-grade TRAEs included anemia [16 patients (37%) and 23 patients (43%), respectively], leukopenia [12 (28%) and 10 (19%)], and neutropenia [9 (21%) and 9 (17%); Supplementary Table S5, available at https://doi.org/10.1016/j.esmoop.2023.102040], and the most common grade 3-4 TRAE (occurring in ≥15% of patients in either treatment arm) was neutropenia [8 (19%) and 8 (15%)]. Treatment discontinuation due to TRAEs occurred in four patients (9%) treated with nivolumab plus chemotherapy and three patients (6%) treated with chemotherapy alone (Table 3). The incidence of IMAEs was low, and events were mostly grade 1-2 in severity (Supplementary Table S6, available at https://doi.org/10.1016/j.esmoop.2023.102040); IMAEs occurred in <10% of patients in the nivolumab plus chemotherapy arm, with the most common IMAE being rash [three patients (7%)]. Among patients who underwent definitive surgery, 28 (78%) in the nivolumab plus chemotherapy arm and 34 (83%) in the chemotherapy arm reported surgery-related AEs, including five (14%) and nine (22%), respectively, who experienced grade 3-4 surgery-related AEs (Table 3). Only one treatment-related death due to pneumonia occurred in the chemotherapy arm.
Table 3.
Safety summary in the Chinese subpopulation
| Nivolumab plus chemotherapy (n = 43) |
Chemotherapy (n = 53) |
|||
|---|---|---|---|---|
| Any grade | Grade 3-4 | Any grade | Grade 3-4 | |
| Any-cause AEsa,b | ||||
| All | 42 (98) | 20 (46) | 51 (96) | 23 (43) |
| Leading to treatment discontinuation | 4 (9) | 4 (9) | 3 (6) | 0 |
| Serious | 8 (19) | 3 (7) | 4 (8) | 2 (4) |
| TRAEsa,c | ||||
| All | 38 (88) | 18 (42) | 47 (89) | 22 (42) |
| Leading to treatment discontinuation | 4 (9) | 4 (9) | 3 (6) | 0 |
| Serious | 7 (16) | 3 (7) | 4 (8) | 2 (4) |
| Surgery-related AEsd | 28 (78) | 5 (14) | 34 (83) | 9 (22) |
| Treatment-related deaths | 0 | — | 1 (2)e | — |
Data reported as n (%). AEs per CTCAE version 4.0 and MedDRA version 25.0.
AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; MedDRA, Medical Dictionary for Regulatory Activities; TRAE, treatment-related adverse event.
Reported events occurred between the first dose and 30 days after the last dose of neoadjuvant study treatment.
No grade 5 AEs were reported in either treatment arm.
No grade 5 TRAEs were reported in either treatment arm.
Reported events occurred within 90 days after definitive surgery. Denominators are based on patients who underwent definitive surgery (nivolumab plus chemotherapy, n = 36; chemotherapy, n = 41). No grade 5 surgery-related AEs were reported in either treatment arm.
Treatment-related death due to pneumonia.
Discussion
To our knowledge, the present exploratory analysis is the first to report clinical outcomes with neoadjuvant immunotherapy in Chinese patients with resectable NSCLC from a phase III study. At 3 years' minimum follow-up, nivolumab plus chemotherapy improved EFS and pCR versus chemotherapy alone in the Chinese subpopulation of CheckMate 816. Favorable outcomes were also observed with respect to MPR, TTDM, EFS2, and ORR in the nivolumab plus chemotherapy versus the chemotherapy arms. Moreover, surgical outcomes were similar between treatment arms in the Chinese subpopulation, suggesting that the addition of neoadjuvant nivolumab to chemotherapy did not impact the feasibility of surgery. Nivolumab plus chemotherapy did not substantially increase the incidence or severity of TRAEs or surgery-related AEs compared with chemotherapy alone in the Chinese subpopulation, and no new safety signals were observed. Although greater proportions of patients in the Chinese subpopulation underwent pneumonectomy and/or had R0 resection compared with the global concurrently randomized population, which may be indicative of varying surgical practices across geographical regions,29, 30, 31 in general, efficacy, safety, and surgical outcomes with nivolumab plus chemotherapy in the Chinese subpopulation were consistent with those in the global study population.9,17
Consistent clinical benefit with nivolumab plus chemotherapy was observed across most subgroups in the Chinese subpopulation. Notably, numerical improvements in EFS and pCR with nivolumab plus chemotherapy versus chemotherapy alone were observed in patients with either stage IB-II or stage IIIA NSCLC and in patients with either squamous or non-squamous disease. The magnitude of EFS and pCR benefit with nivolumab plus chemotherapy was more pronounced in patients with tumor PD-L1 ≥1% than in those with tumor PD-L1 <1%. These findings, however, need to be interpreted with caution due to small subgroup sample sizes and potential imbalances in patient groups between treatment arms.
Findings from the present analysis of neoadjuvant nivolumab plus chemotherapy were generally similar to those reported with other anti-PD-1-based treatment regimens in phase I and phase II studies evaluating Chinese patients with resectable NSCLC.32, 33, 34, 35 An interim analysis of the phase III Neotorch study, which evaluated Chinese patients with resectable stage III non-squamous NSCLC (median follow-up, 18.3 months), recently showed improvements in EFS and pCR with perioperative toripalimab plus chemotherapy followed by maintenance toripalimab monotherapy versus perioperative chemotherapy,36 further emphasizing the role of neoadjuvant immunotherapy-based treatment regimens before surgery. Whereas cross-trial comparisons are limited by various factors, such as differences in trial designs, evaluated treatments, and enrolled patient populations, the relatively large proportion of Chinese patients evaluated in CheckMate 816 and the randomized, comparative nature of this phase III study enabled long-term subpopulation analyses that provided greater insight into the potential impact of race and ethnicity on clinical outcomes. The efficacy and safety of nivolumab plus chemotherapy reported here highlight the benefit of immunotherapy-based treatment regimens in Chinese patients with resectable NSCLC.
It is important to note that ethnicity and geographic region were not stratification factors for CheckMate 816. Although outcomes in the Chinese subpopulation were similar to those in the global study population of CheckMate 816,9,17 caution should be exercised when interpreting these results due to the potential of unknown confounding factors. Additionally, this post hoc analysis of the Chinese subpopulation was limited by small sample sizes, impacting the interpretation and generalizability of data.
Consistent with findings in the global study population of CheckMate 816,9,17 neoadjuvant nivolumab plus chemotherapy demonstrated clinically meaningful efficacy in Chinese patients with resectable NSCLC. Neoadjuvant nivolumab plus chemotherapy did not impact treatment tolerability or the feasibility of surgery in the Chinese subpopulation. These findings support the use of nivolumab plus chemotherapy as a standard neoadjuvant treatment of Chinese patients with resectable NSCLC.
Acknowledgements
This work was supported by Bristol Myers Squibb. We thank the patients and families who made this trial possible, the investigators and clinical study teams who participated in this trial, and Dako, an Agilent Technologies company, for collaborative development of the PD-L1 IHC 28-8 pharmDx assay. Medical writing and editorial support for the development of this manuscript, under the direction of the authors, was provided by Adel Chowdhury, PharmD, and Michele Salernitano, of Ashfield MedComms, an Inizio company, funded by Bristol Myers Squibb.
Funding
This work was supported by Bristol Myers Squibb (no grant number).
Disclosure
CW reports receiving meeting travel/registration support from Bristol Myers Squibb; serving on advisory boards for Bristol Myers Squibb; and holding leadership positions for Chinese Society of Clinical Oncology and National Health Commission Capacity Building and Continuing Education. IN is an employee and stockholder of Bristol Myers Squibb. JC is an employee and stockholder of Bristol Myers Squibb; and reports receiving meeting travel/registration support from Bristol Myers Squibb. JB is an employee and stockholder of Bristol Myers Squibb. PT is an employee and stockholder of Bristol Myers Squibb. SL reports receiving advisory/consulting fees from AstraZeneca, Boehringer Ingelheim, GenomiCare, Hutchison MediPharma, Roche, Simcere, and Zai Lab; and receiving speaker fees from AstraZeneca, Hansoh, and Roche. All other authors have declared no conflicts of interest.
Data Sharing
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Contributor Information
C. Wang, Email: wangchangli@tjmuch.com.
S. Lu, Email: shun_lu@hotmail.com.
Supplementary data
References
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