Abstract
Objective
Studies have suggested the potential efficacy of immune checkpoint inhibitors (ICIs) for pulmonary sarcomatoid carcinoma. This multicenter observational study was conducted to evaluate the efficacy of systemic ICI therapy and chemoradiation followed by durvalumab therapy for pulmonary sarcomatoid carcinoma.
Methods
We analyzed the data of patients with pulmonary sarcomatoid carcinoma who received systemic ICI therapy or chemoradiation followed by durvalumab therapy between 2016 and 2022.
Results
In this study, data of a total of 22 patients who received systemic ICI therapy and four patients who received chemoradiation followed by durvalumab therapy were analyzed. In the patients who received systemic ICI therapy, the median progression‐free survival after initiation of therapy was 9.6 months, and the overall survival did not reach the median. The 1‐year progression‐free survival rate and overall survival rate were estimated to be 45.5% and 50.1%, respectively. Although the log‐rank test revealed no significant association between the tumor expression level of programmed death ligand‐1 (tumor proportion score evaluated using 22C3 antibody: ≥50% vs. <50%) and the survival duration, the majority of patients showing long‐term survival showed a tumor proportion score of ≥50%. Of four patients treated with chemoradiation followed by durvalumab therapy, two patients showed an overall survival of ≥30 months, whereas the remaining two patients died within 12 months.
Conclusion
The progression‐free survival of patients who received systemic ICI therapy was 9.6 months, suggesting that ICI therapy might be effective in patients with pulmonary sarcomatoid carcinoma.
Keywords: immune checkpoint inhibitor, pleomorphic carcinoma, survival, treatment
This multicenter observational study evaluated the clinical course of patient with sarcomatoid carcinoma treated with systemic immune checkpoint inhibitor therapy or chemoradiation followed by durvalumab therapy. The median progression‐free survival was 9.6 months and the overall survival did not reach the median in 22 patients with pulmonary sarcomatoid carcinoma who received systemic immune checkpoint inhibitor therapy. Of four patients treated with chemoradiation followed by durvalumab therapy, two patients showed an overall survival of ≥30 months, whereas the remaining two patients died within 12 months. It is suggested that immune checkpoint inhibitor therapy may improve the prognosis in patients with pulmonary sarcomatoid carcinoma. However, the results also suggested that there could be treatment‐resistant cases.
INTRODUCTION
Pulmonary sarcomatoid carcinoma is defined as non–small cell lung cancer (NSCLC) with sarcomatous components. It accounts for 1% of all lung cancers, and is classified into pleomorphic carcinoma, spindle cell carcinoma, giant cell carcinoma, carcinosarcoma, or pulmonary blastoma. 1 It is resistant to treatment with cytotoxic agents, and the overall survival (OS) after initiation of systemic treatment with cytotoxic agents has been estimated to range from 5 to 8 months, on average. 2 , 3 , 4 A phase II trial suggested that combined administration of a vascular endothelial growth factor inhibitor and cytotoxic agent might be effective, but the efficacy is limited, as the median progression‐free survival (PFS) and OS have been estimated to be 4.2 months and 11.2 months, respectively. 5
Recently, immune checkpoint inhibitors (ICIs) have been shown to confer survival benefit in patients with NSCLC. Cytotoxic agents have been used as the standard therapy for NSCLC patients without driver mutations, but the efficacy is limited, with a reported 2‐year survival rate of 18.9% in patients treated with cisplatin plus pemetrexed. Pembrolizumab monotherapy, however, was associated with a 5‐year survival rate of 31.9% in patients with NSCLC showing strong tumor expression of programmed death ligand‐1 (PD‐L1) 6 and combined therapy with ICIs and cytotoxic agents has been shown to be effective, regardless of the tumor PD‐L1 expression status. 7 , 8 There are also a few case reports suggesting the efficacy of ICI therapy in patients with pulmonary sarcomatoid carcinoma. 9 , 10 , 11 , 12 , 13 , 14 , 15 In some of these case reports, the treatment duration with ICIs exceeded 6 months. However, on account of publication bias, evaluation of consecutive cases would be desirable to confirm the efficacy of ICI therapy in patients with pulmonary sarcomatoid carcinoma.
A phase III trial conducted in patients with locally advanced NSCLC revealed an improved PFS and OS in patients who received chemoradiation followed by durvalumab therapy as compared with patients who received chemoradiation therapy alone. 16 However, there are few reports of responses to chemoradiation with or without durvalumab therapy in patients with pulmonary sarcomatoid carcinoma. 4 , 17 , 18 , 19 , 20
We conducted this observational study to evaluate the efficacy of systemic ICI therapy and chemoradiation followed by durvalumab therapy in patients with advanced and locally advanced pulmonary sarcomatoid carcinoma.
METHODS
Patients
The clinical data of patients with pulmonary sarcomatoid carcinoma diagnosed at Toyama University Hospital, Toyama Prefectural Central Hospital, or Toyama Red Cross Hospital were collected using Research Electronic Data Capture (REDCap), and a database was constructed. Of these, the data of patients who fulfilled the following criteria were extracted for the analyses in the present study: (1) patients diagnosed as having pulmonary sarcomatoid carcinoma; (2) patients who received systemic ICI therapy, including ICI monotherapy, combined ICI plus cytotoxic agent therapy, or ICI doublet therapy (nivolumab plus ipilimumab), or chemoradiation followed by durvalumab therapy. Both data of patients in whom the diagnosis was confirmed by histopathological examination of surgical or autopsy specimens and data of patients who were clinically diagnosed as having pulmonary sarcomatoid carcinoma by biopsy were included.
This study was conducted in compliance with the principles laid down in the Declaration of Helsinki and Ethical Guidelines for Medical and Biological Research Involving Human Subjects (Ministry of Health, Labour and Welfare, Japan), with the approval of the Ethics Committee, University of Toyama (approval number: R2020099). Because we only analyzed the clinical information of the patients in this study, without resorting to any invasion or therapeutic intervention, the need to obtain informed consent was waived, although information about the study was disclosed to the participants, under the approval of the Ethics Committee，University of Toyama.
Clinical information
Information on the age, performance status (PS), and metastatic sites was extracted at the time of initiation of the systemic ICI or chemoradiation therapy. Presence/absence of driver mutations and the tumor PD‐L1 expression status were evaluated at any time point during the clinical course. Evaluation of tumor PD‐L1 expression was commissioned to a commercial laboratory, and it was evaluated by determining the tumor proportion score (TPS) using the 22C3 antibody. Disease progression was defined according to the Response Evaluation Criteria in Solid Tumors version 1.1 and/or based on clinical judgment.
Treatment
The treatment regimen for each patient was decided based on the clinical judgment. ICI monotherapy (pembrolizumab or nivolumab), combined ICI plus cytotoxic agent therapy (platinum doublet plus atezolizumab, pembrolizumab, or nivolumab plus ipilimumab), and ICI doublet therapy (nivolumab plus ipilimumab) were administered. Patients were treated with the standard doses and schedules and treatment interruption or discontinuation was determined by the attending physician.
Statistical analysis
The endpoints of the present study were the PFS and OS. PFS was calculated from the day of initiation of the systemic therapy with ICIs or chemoradiation until disease progression or death due to any cause, and censored on the day of the last visit before disease progression or death. OS was calculated from the day of initiation of the systemic therapy with ICIs or chemoradiation until death due to the any cause, and censored on the day of the last visit before death. Kaplan–Meier survival curves were constructed to determine the survival rates and the survival durations between patient groups divided by the tumor PD‐L1 expression level were compared using the log‐rank test. All statistical analyses were performed using the statistical software package JMP ver. 15.0.0 (SAS).
RESULTS
Systemic therapy with ICIs
A total of 22 patients with advanced pulmonary sarcomatoid carcinoma received systemic therapy with ICIs between 2016 and 2022 (Appendix S1).
Table 1 shows the patient characteristics. The median (range) age was 68.5 (40–84) years, and 10 patients (45.5%) were 70 years or older. Diagnosis of sarcomatoid carcinoma was confirmed by histopathological examination of specimens obtained at surgery (10 patients, 45.5%), by surgical biopsy (one patient, 4.5%), by needle biopsy (six patients, 27.3%), or by transbronchial biopsy (five patients, 22.7%). Three patients (13.6%) previously received chemoradiation followed by durvalumab therapy. The tumor PD‐L1 expression was evaluated in 18 patients, of which 16 patients (72.7%) were positive for tumor PD‐L1 expression (TPS ≥1%), and 11 patients (50.0%) had a PD‐L1 TPS of ≥50%. ICI therapy was administered as first line therapy in 14 (63.6%) patients and as second‐ or subsequent‐line therapy in eight (36.4%) patients. ICI monotherapy, combined ICI plus cytotoxic agent therapy, and ICI doublet therapy (nivolumab plus ipilimumab) were administered in 15 (68.2%), six (27.3%), and one (4.5%) patients, respectively.
TABLE 1.
Characteristics of patients who received systemic therapy with ICIs
| n | % | ||
|---|---|---|---|
| No. of patients | 22 | ||
| Sex | Male | 19 | 86.4 |
| Age (years) | ≥70 | 10 | 45.5 |
| Smoking history | Yes | 20 | 90.9 |
| PS | 0–1 | 15 | 68.2 |
| ≥2 | 6 | 27.3 | |
| Unknown | 1 | 4.5 | |
| Diagnostic procedure | Surgery | 10 | 45.5 |
| Surgical biopsy | 1 | 4.5 | |
| Needle biopsy | 6 | 27.3 | |
| TBB | 5 | 22.7 | |
| EGFR | Wild‐type | 20 | 90.9 |
| Unknown | 2 | 9.1 | |
| ALK | Wild‐type | 16 | 72.7 |
| Unknown | 6 | 27.3 | |
| ROS1 | Wild‐type | 12 | 54.5 |
| Unknown | 10 | 45.5 | |
| BRAF | Wild‐type | 9 | 40.9 |
| Unknown | 13 | 59.1 | |
| MET | Mutant | 2 | 9.1 |
| Wild‐type | 8 | 36.4 | |
| Unknown | 12 | 54.5 | |
| PD‐L1 | <50% | 7 | 31.8 |
| ≥50% | 11 | 50.0 | |
| Unknown | 4 | 18.2 | |
| Remote metastasis | Brain | 4 | 18.2 |
| Liver | 1 | 4.5 | |
| Adrenal gland | 3 | 13.6 | |
| Bone | 6 | 27.3 | |
| Lymph node | 2 | 9.0 | |
| ICI regimen | ICI monotherapy | 15 | 68.2 |
| Cytotoxic agents + ICI | 6 | 27.3 | |
| ICI doublet | 1 | 4.5 | |
| Treatment line of ICI therapy | 1st line | 14 | 63.6 |
| ≥2nd line | 8 | 36.4 |
Abbreviations: ALK, anaplastic lymphoma kinase; BRAF, v‐raf murine sarcoma viral oncogene homolog B; EGFR, epidermal growth factor receptor; ICI, immune checkpoint inhibitors; MET, mesenchymal‐epithelial transition; PD‐L1, programmed death ligand‐1; PS, performance status; ROS1, ROS proto‐oncogene 1; TBB, transbronchial biopsy.
Figure 1 shows the Kaplan–Meier curves for the PFS and OS after the initiation of the systemic therapy with ICIs. The median (95% confidence interval [CI]) PFS was 9.6 (1.2–not estimated) months. The OS did not reach the median value. The 1‐year PFS rate (95% CI) and OS (95% CI) rate were 45.5% (25.2%–67.4%) and 50.1% (27.5%–72.7%), respectively, and the 5‐year PFS rate (95% CI) and OS rate (95% CI) were 31.2% (13.6%–56.6%) and 50.1% (27.5%–72.7%), respectively.
FIGURE 1.
Kaplan–Meier curve for PFS and OS after the initiation of systemic treatment with immune checkpoint inhibitors. OS, overall survival; PD‐L1, programmed death ligand‐1; PFS, progression‐free survival
Figure 2 shows the association between the tumor PD‐L1 expression level and survival. Data of 18 patients in whom the tumor PD‐L1 expression level was evaluated were analyzed. There was no significant association between the tumor PD‐L1 expression level and either the PFS (p = 0.422, log‐rank test) or the OS (p = 0.377, log‐rank test).
FIGURE 2.
Kaplan–Meier curve for PFS and OS after the initiation of systemic treatment with immune checkpoint inhibitors according to the tumor PD‐L1 expression level. Solid line: PD‐L1 tumor proportion score (TPS) ≥50%, dashed line: PD‐L1 TPS <50%. CBDCA, carboplatin; OS, overall survival; PTX, paclitaxel; PD‐L1, programmed death ligand‐1; PFS, progression‐free survival
Chemoradiation followed by durvalumab therapy
Between 2016 and 2022, four patients with pulmonary sarcomatoid carcinoma received chemoradiation followed by durvalumab therapy. Table 2 shows the patient characteristics and clinical course. Three patients received chemoradiation with carboplatin plus paclitaxel therapy, and one patient received chemoradiation with carboplatin therapy. Disease progression was eventually observed in all patients who received chemoradiation and durvalumab therapy. Of these, two patients died within 12 months, and the remaining two patients survived for more than 30 months.
TABLE 2.
Patient characteristics and clinical course of patients who received chemoradiation plus durvalumab therapy
| Sex | Age (years) | PS | Smoking history | Diagnostic procedure | Driver mutation | PD‐L1 TPS (%) | Stage | Regimen | PFS (months) | OS (months) |
|---|---|---|---|---|---|---|---|---|---|---|
| M | 74 | 1 | Yes | Autopsy | Negative/unknown | 10 | IIIB | CBDCA+PTX | 3.3 | 5.2 |
| M | 66 | 1 | Yes | Needle biopsy | Negative/unknown | 40 | IIIA | CBDCA+PTX | 3.6 | 7.3 |
| F | 82 | 1 | No | Surgery | MET | 35 | IIB | CBDCA | 8.2 | 30.6 |
| M | 59 | 1 | Yes | Needle biopsy | Negative/unknown | 10 | IIIB | CBDCA+PTX | 22.9 | 32.5 a |
Abbreviations: CBDCA, carboplatin; F, female; M, male; OS, overall survival; PD‐L1, programmed death ligand‐1; PFS, progression‐free survival; PS, performance status; PTX, paclitaxel; TPS, tumor proportion score.
Alive.
DISCUSSION
In the present study, we evaluated the clinical courses of patients with pulmonary sarcomatoid carcinoma who received systemic therapy with ICIs or chemoradiation followed by durvalumab therapy. In patients who received systemic therapy with ICIs, the 1‐year OS rate was 50.1%. As for chemoradiation followed by durvalumab therapy, the OS in two of the four patients was more than 30 months, whereas the remaining two patients died within 1 year.
Recently, two observational studies evaluated the efficacy of ICI therapy in patients with pulmonary sarcomatoid carcinoma. 21 , 22 Domblides et al.21 analyzed the data of 37 patients with pulmonary sarcomatoid carcinoma who received ICI monotherapy, including 32 patients in whom the diagnosis was confirmed by biopsy or cytology. They reported a median (range) PFS and OS in the patients of 4.89 (0.3–35.7) months and 12.7 (0.3–45.7) months, respectively. The 1‐year survival rate was 51.3%. Lee et al.22 reported a median (95% CI) PFS and OS of 7.2 (4.9–9.5) months and 22.2 (7.0–37.3) months, respectively, in 49 patients with pulmonary sarcomatoid carcinoma who received ICI monotherapy. These figures are comparable to our findings, but the survival duration of the patients in our study was slightly longer. The difference could potentially be explained by the small sample size. However, in the present study, a larger number of patients (14, 63.6%) received ICIs as first‐line treatment than in previous studies, and seven (31.8%) patients, in particular, received combined therapy with ICIs plus cytotoxic agents, whereas patients in the previously reported studies received only ICI monotherapy; this could explain, at least in part, the prolonged PFS.
In the present study, we found no significant association between the tumor PD‐L1 expression level and survival, and even some patients with a PD‐L1 TPS of ≥50% showed early progression or death. However, a possible association cannot be excluded, because a majority of the patients who showed a long survival showed a PD‐L1 TPS of ≥50%. In one previously reported study, the tumor PD‐L1 expression level was associated with the PFS in patients with pulmonary sarcomatoid carcinoma who had received ICI monotherapy. 22 However, there could also be other factors that could independently affect the efficacy of ICIs. Domblides et al. 21 investigated the association between the tumor mutation burden and survival.
There are a few published reports of the effects of chemoradiation against pulmonary sarcomatoid carcinoma. Yorozuya et al.19 and Shimamura et al.20 reported a PFS of ≥12 months and 10 months, respectively, in patients with pulmonary sarcomatoid carcinoma treated with chemoradiation followed by durvalumab therapy. In the present study also, the OS was longer than 30 months in two of the four patients who received this therapy. However, the remaining two patients died within 1 year, suggesting that some cases could be treatment‐resistant. The synergistic effect of durvalumab with chemoradiotherapy in patients with pulmonary sarcomatoid carcinoma has not yet been fully investigated. According to previous reports, the OS varied over a wide range in patients with pulmonary sarcomatoid carcinoma who received chemoradiation alone without durvalumab therapy. Although a poor outcome with a median OS of 3 months has been reported, 17 patients showing 2‐year survival 18 and 5‐year survival 4 have also been reported. Therefore, the additive benefit of durvalumab therapy combined with chemoradiation in patients with pulmonary sarcomatoid carcinoma is currently unclear.
The present study had several limitations. First, because the study sample was small, there is a problem in regard to generalization of the results. Second, the previous World Health Organization (WHO) classification of pulmonary sarcomatoid carcinoma was based on the histopathology of resected specimens. The 2015 WHO classification was the first to classify lung cancers based on the results of biopsy, and it is recommended that NSCLC showing sarcomatoid components in small biopsy specimens be diagnosed as non–small cell carcinoma with spindle cell and/or giant cell carcinoma. 1 The present study, similar to previous ones, included patients diagnosed based on biopsy specimens. Therefore, to be precise, the study subjects of the present study were patients who were diagnosed as having pulmonary sarcomatoid carcinoma or non–small cell carcinoma with spindle cell and/or giant cell carcinoma. However, many cases of advanced pulmonary sarcomatoid carcinoma are assumed to be diagnosed by biopsy in clinical practice. Therefore, we consider that in the present study, we evaluated the actual situation of patients clinically diagnosed as having pulmonary sarcomatoid carcinoma in clinical settings. Finally, we could not elucidate the effect of ICI therapy on immune cells in pulmonary sarcomatoid carcinoma and the differences in immune cell responses between responders and non‐responders. These are important research issues and evaluation of the tumor microenvironment may be useful for these analyses.
In summary, the present study showed that ICI therapy may improve the prognosis in patients with pulmonary sarcomatoid carcinoma. However, the results also suggested that there could be treatment‐resistant cases. A study to identify predictors of the efficacy of ICI therapy for pulmonary sarcomatoid carcinoma and development of novel therapies are warranted.
AUTHOR CONTRIBUTIONS
Minehiko Inomata wrote the main manuscript text. Takeshi Tsuda, Tomomi Ichikawa, Seisuke Okazawa, and Ryuji Hayashi contributed to editing the draft. Masahiro Matsumoto, Isami Mizushima, Kenji Azechi, Naoki Takata, Nozomu Murayama, Kana Hayashi, Takahiro Hirai, Zenta Seto, Kotaro Tokui, Yasuaki Masaki, Chihiro Taka, Kenta Kambara, Shingo Imanishi, Hirokazu Taniguchi, Toshiro Miwa, and Shoko Matsui contributed to data collection. Kazuyuki Tobe supervised the study. All authors approved the final version of the manuscript.
CONFLICT OF INTEREST STATEMENT
Authors declare no conflict of interest that might be relevant to the contents of this manuscript.
Supporting information
Appendix S1. Supplementary File.
ACKNOWLEDGMENTS
We are grateful to the Center for Clinical Research, Toyama University Hospital, for their support with the use of REDCap. This research received no specific grant from any funding agency in the public, commercial, or not‐for‐profit sectors.
Inomata M, Tsuda T, Ichikawa T, Matsumoto M, Mizushima I, Azechi K, et al. Efficacy of immune checkpoint inhibitor therapy in patients with pulmonary sarcomatoid carcinoma in clinical practice. Thorac Cancer. 2023;14(17):1618–1623. 10.1111/1759-7714.14907
DATA AVAILABILITY STATEMENT
All data generated or analyzed during this study are included in this published article and its supplementary information files.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Appendix S1. Supplementary File.
Data Availability Statement
All data generated or analyzed during this study are included in this published article and its supplementary information files.