Initial evaluation of nivolumab in patients with post-operative recurrence of malignant pleural mesothelioma

Abstract

Background

Limited options exist for treating post-recurrence patients with malignant pleural mesothelioma (MPM). This study aimed to evaluate the efficacy and feasibility of nivolumab in patients with post-operative recurrence of MPM in a real-world setting.

Methods

This study included 35 patients with post-operative recurrence of MPM. Treatment consisted of 240-mg intravenous nivolumab administration every 2 weeks until progressive disease (PD) or serious adverse events (AEs). Additional post-treatment data were evaluated, including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), post-treatment survival and AEs. Tumor response was assessed using the modified Response Evaluation Criteria in Solid Tumors. Survival analysis was performed using the Kaplan–Meier method. The feasibility analysis including AEs was performed with the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Results

Of the 35 patients who received nivolumab, median follow-up was 6 months. The median treatment duration was 3 months (range: 1–14 months), and median of 8 cycles (range: 2–32 cycles) was administered. Best overall responses were follows: 1 patient had complete response, 6 had partial response, 18 had stable disease and 8 had PD. The ORR was 20.0%, and the DCR was 77.1%. The median overall survival and PFS were 13.1 and 4.4 months, respectively. There were grade-3 AEs in four patients (11.4%). No grade-4 or -5 AEs were observed.

Conclusion

Nivolumab treatment in patients with post-operative recurrence of MPM seems safe and clinical efficacy.

malignant pleural mesothelioma, nivolumab, post-operative recurrence, programmed death-1 inhibition, adverse events

Introduction

Malignant pleural mesothelioma (MPM) is an aggressive tumor; most patients exhibit recurrence after multimodality treatment (1). There are two types of curative-intent surgeries for MPM, including pleurectomy/decortication (P/D) and extrapleural pneumonectomy (EPP). Both P/D and EPP are highly invasive surgeries, with poor performance status (PS) in patients with post-operative recurrence of MPM (2). Furthermore, in many cases, post-recurrence treatment is challenging owing to lack of evidence. Currently, only one treatment regimen is approved by the United States Food and Drug Administration: cisplatin and pemetrexed. No second-line systemic therapy has been approved in the USA and many other countries (3).

The MERIT (multicenter, open-label, single-arm, Japanese phase 2 study in MPM) confirmed that programmed death-1 (PD-1) inhibition is active in MPM and led to the regulatory approval of nivolumab for the second-line treatment of MPM in Japan in August 2018 (4). In the future, this therapy is expected to improve the treatment results in patients with MPM with the use of nivolumab. To our knowledge, no clinical studies have investigated the efficacy of nivolumab in patients with post-operative recurrence of MPM. This study aimed to evaluate the efficacy and feasibility of nivolumab in patients with post-operative recurrence of MPM.

Materials and methods

Patient data and treatment

Before recurrence, all the patients underwent multimodality treatment, including curative-intent surgery for MPM. The multimodality treatment was performed as per previous reports (5–7). All the patients received neoadjuvant chemotherapy before curative-intent surgery (P/D or EPP). Neoadjuvant chemotherapy comprised three cycles of platinum-based doublet chemotherapy. After the neoadjuvant chemotherapy, curative-intent surgery (P/D or EPP) was performed for the above patients. Partial pleurectomy (macroscopic residual disease) was decided according to intraoperative findings such as diffuse tumor invasion. Adjuvant-dose hemithoracic irradiation was performed after EPP; alternatively, adjuvant chemotherapy comprising three cycles of platinum-based doublet was administered after P/D. All the patients underwent physical and blood examinations for tumor markers as well as computed tomography (CT) imaging every 3–6 months at our outpatient treatment facility. The recurrence diagnosis and decisions regarding post-recurrence treatment were taken by a cancer board that included a multidisciplinary team.

From August 2018, nivolumab administration was started for patients with post-operative recurrence for MPM. This study included a retrospective review of medical records from a prospectively. We administered nivolumab in the following cases: first, progression after post-recurrence or adjuvant chemotherapy including platinum-based combination treatment with pemetrexed; and second, for patients who did not respond to the neoadjuvant chemotherapy. Nivolumab (240 mg) was administered intravenously on day 1 of a 14-day cycle until progressive disease (PD) or unacceptable toxicity.

Outcome evaluation and statistical analyses

This study was designed as a retrospective cohort study. Patients were followed until death or last contact. Treatment response was assessed using radiological imaging as per a modified version of the Response Evaluation Criteria in Solid Tumors (mRECIST) based on CT or [18F] fluorodeoxy-D-glucose positron emission tomography (FDG-PET)/CT (8). Patients were followed up every 6–12 weeks with radiological imaging during nivolumab treatment.

The outcome was assessed as stable disease (SD), PD, partial response (PR) or complete response (CR). The objective response rate (ORR) was the percentage of patients whose best overall response was CR and PR. The disease control rate (DCR) was the percentage of patients whose best overall response was CR, PR or SD.

Overall survival (OS) rates were calculated from the time of administration of the first nivolumab dose for MPM to the date of the most recent follow-up or death. Progression-free survival (PFS) rates were calculated from the time of administration of the first nivolumab dose for MPM to the date of the most recent follow-up or PD. OS and PFS were estimated using the Kaplan–Meier method. Analyses were performed using JMP 14 (SAS Institute Inc., Cary, NC, USA).

In order to evaluate safety, adverse events (AEs) were graded as per the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v5.0) guidelines (9).

Ethics

All the eligible patients were included in the program after they provided informed consent. The institutional review board at the Hyogo College of Medicine (number 3287) approved the study on 4 September 2019. We collected the medical records, including the radiological data, of all the enrolled patients.

Results

Patient characteristics

Total 35 patients who received nivolumab for post-operative recurrence of MPM between August 2018 and December 2019 were enrolled; thus, the study population included 31 men and 4 women with a median age of 69 years (range: 56–78 years). All the patients completed neoadjuvant chemotherapy; 24 underwent P/D, 6 underwent EPP and 5 underwent partial pleurectomy (macroscopic residual disease) because of tumor extension at our institution. The histological subtypes on final pathology were epithelioid in 32 patients, biphasic in 2 patients and sarcomatoid in 1 patient. As per the pathological stages of the International Mesothelioma Interest Group staging system (version 8), 7 patients had Stage IA, 11 had Stage IB, 2 had Stage II, 9 had Stage IIIA, 5 had Stage IIIB and 1 had Stage IV disease. Total 24 patients (68.6%) completed multimodality treatment, including ≥3 cycles of AC or hemithoracic irradiation. The median time to recurrence after surgery was 16 months. The sites of first recurrence were local (ipsilateral hemithorax or the mediastinum) in 22 patients and distant (abdomen or contralateral hemithorax, brain, bone and so on) in 7 patients. Both local and distant recurrence occurred in 6 patients; 8 patients (22.9%) had only focal recurrence. About 23 patients (65.7%) had undergone post-recurrence treatments before the administration of nivolumab. The initial post-recurrence treatment included ≥3 cycles of chemotherapy (n = 20), surgery (n = 1), radiation therapy (n = 1) and radiofrequency ablation (n = 1). Before the administration of nivolumab, 21 patients received chemotherapy for post-operative recurrence. As the first-line systemic treatment for post-operative recurrence, 20 received a platinum agent plus pemetrexed and 1 received single-agent pemetrexed. As second-line systemic treatment or PD after the first-line treatment, 6 received single-agent pemetrexed, 3 received irinotecan plus gemcitabine and 4 received other regimens. About 14 patients received nivolumab as the first-line systemic treatment for post-operative recurrence. Of the 35 patients who received nivolumab for post-operative recurrence, 11 had an Eastern Cooperative Oncology Group PS of 0, 21 had 1 and 3 had 2 at the time of nivolumab administration. The demographic features and disease characteristics of the patients are summarized in Table 1.

Table 1

Clinical characteristics of the patients (n = 35)

Characteristics	Value
Age, years, median (range)	69 (56–78)
Sex
Male	31 (88.6%)
Female	4
Surgery
Pleurectomy/decortication	24 (68.6%)
Extrapleural pneumonectomy	6
Partial pleurectomy	5
Pathology
Epithelioid	32 (91.4%)
Biphasic	2
Sarcomatoid	1
Stage (IMIG 8th edition)
IA/IB/II/IIIA/IIIB/IV	7/11/2/9/5/1
Multimodality treatment
Completed	24 (68.6%)
Uncompleted	11
Performance status at the administration of nivolumab
0	11 (60.0%)
1	21
2	3
Initial recurrence pattern
Local	22 (62.9%)
Distant	7
Both (local + distant)	6
Previous treatments (initial post-recurrence treatment)
Present	23 (65.7%)
Chemotherapy	20
Surgery	1
Radiotherapy	1
Radiofrequency ablation	1
Absent	12
Post-recurrence chemotherapy before nivolumab
Present	21 (60.0%)
Absent	14
Regimen (Post-recurrence chemotherapy before nivolumab)
First line
CDDP or CBDCA/PEM	20
PEM	1
Second line
PEM	6
GEM/CPT-11	3
CDDP/DOC	1
5FU-NDP	1
CBDCA/GEM	1
GEM	1
Third line
VNR	2
CDDP/PEM	1
GEM	1
Forth line
PEM	1

IMIG: International Mesothelioma Interest Group, CDDP: cisplatin, CBDCA: carboplatin, PEM: pemetrexed, GEM: gemcitabine, CPT-11: irinotecan, DOC: docetaxel, 5FU: 5-fluorouracil, NDP: nedaplatin, VNR: vinorelbine.

Figure 1.

Overall survival (OS) and progression-free survival (PFS). (A) Kaplan–Meier curves of OS from the time of first nivolumab. The 12-month survival rate was 54.1%. (B) Kaplan–Meier curves of PFS from the time of first nivolumab. The 12-month PFS rate was 17.1%.

Figure 2.

The swimmer’s plot (B) shows the treatment duration and response duration, with the bar length corresponding to the duration of follow-up for each patient (n = 35). Results are at data cutoff. Four patients (No. 15, 17, 25, 35) were led to discontinuation of nivolumab treatment temporarily by adverse events (AEs), restarting the administration of nivolumab after recovery of AEs. Red triangles show progressive disease. Red crosses show death. Arrows show ongoing treatment at data cutoff.

Efficacy evaluation

The median follow-up time after the start of nivolumab was 6 months (range: 1–14 months). The median treatment duration was 3 months (range: 1–14 months) with a median of 8 cycles (range: 2–32) administered. About 11 of the 35 patients died because of tumor progression, 12 (34.3%) continued nivolumab treatment and 23 stopped treatment. The reasons for discontinuation included PD (n = 19) and toxicities (n = 4).

The best radiological outcomes were CR in 1 patient, PR in 6 patients and SD in 18 patients. Eight patients had PD. The ORR and DCR were 20.0 and 77.1%, respectively (Table 2). The Kaplan–Meier curves for OS and PFS after nivolumab administration are shown in Fig. 1. The median OS in the study was 13.1 months. The 6- and 12-month OS were 78.1 and 54.1%, respectively. Furthermore, the 6- and 12-month PFS rates were 31.9 and 17.1%, respectively (median PFS, 4.4 months). At data cutoff, 11 of the 35 patients (31.4%) had an ongoing response. The median duration of response was 4.4 months, with median time to response 2.0 months. The details of the treatment exposure and response durations of all the patients are shown in Fig. 2.

The DCR by histological subtype was as follows: 75.0% (24 of 32 patients), 0% (0 of 1 patient) and 50.0% (1 or 2 patients) for epithelioid, sarcomatoid and biphasic types, respectively. The one patient with sarcomatoid subtype, the best radiological outcome was PD. Although chest wall masses and intrapulmonary nodules attended to grow larger, adrenal metastasis was reduced significantly. The DCR by recurrence pattern was as follows: 81.8% (18 of 22 patients), 71.4% (5 of 7 patients) and 66.7% (4 or 6 patients) for local, distant and both (local + distant) recurrence, respectively.

Safety evaluation

Toxicity was retrospectively determined for all patients by type using the CTCAE v5.0. Table 3 shows AEs in the 35 patients administered nivolumab. Total 39 AEs were reported in 28 patients (80%), including 4 (11.4%) grade-3 AEs. No grade-4 or grade-5 AEs were observed. There were no episodes of febrile neutropenia or treatment-related deaths. The most common AEs observed were hypothyroidism in 11 patients (31.4%), dermatitis in 5 (14.3%), proteinuria in 3 (8.6%) and amylase increase in 3 (8.6%). Grade-3 interstitial lung disease was observed in 2 patients (5.7%). Thus, nivolumab was stopped, and steroid treatment was initiated. Reasons for discontinuation in the study were interstitial lung disease in 2 patients, autoimmune hemolytic anemia in 1 and mesenteric panniculitis in 1 patient. Although nivolumab was temporarily discontinued in 4 patients because of AEs (proteinuria in 1 patient, hyperthyroidism in 1 patient, duodenal ulcer in 1 patient and herpes zoster in 1 patient), the treatment was restarted after the AEs subsided.

Table 2

Efficacy of nivolumab

	Number (n = 35)
Best overall response number
Complete response	1
Partial response	6
Stable disease	18
Progressive disease	8
Objective response number	7
Disease control number	25

Table 3

Treatment-related adverse events (AEs)

	Number (n = 35)
	Grade 1–2	Grade 3	Grade 4–5
Any AEs (39 AEs in 28 patients)	35	4	0
Hypothyroidism	11	0	0
Dermatitis	5	0	0
Amylase increase	3	0	0
Proteinuria	3	0	0
Weight loss	2	0	0
Lipase increase	2	0	0
Nausea/vomiting	2	0	0
Interstitial lung disease	0	2	0
Autoimmune hemolytic anemia	0	1	0
Duodenal ulcer	0	1	0
Alkaline phosphatase increase	1	0	0
Upper respiratory tract infection	1	0	0
Hyperthyroidism	1	0	0
Mesenteric panniculitis	1	0	0
Herpes zoster	1	0	0
Dizziness	1	0	0
Decreased appetite	1	0	0

Discussion

To the best of our knowledge, this is the first study to examine the clinical outcome of nivolumab in patients with post-operative recurrence of MPM. The present study had the following two important findings. First, nivolumab showed promising efficacy in the treatment of post-operative recurrence of MPM. Overall, there was an ORR of 20.0% and DCR of 77.1%. The median duration of response was 4.4 months with median OS and PFS of 13.1 and 4.4 months, respectively, after nivolumab administration. Second, regarding the safety result of nivolumab in this study, of the 35 patients who were administered nivolumab, only 4 (11.4%) experienced grade-3, grade-4 or grade-5 AEs, providing acceptable outcomes in spite of post-multimodality treatment, including highly invasive surgeries.

MPM is an aggressive tumor in which most patients exhibit recurrence after multimodality treatment (1, 7). We have previously reported on the post-recurrence treatment for MPM. The survival time was significantly longer in patients who received post-recurrence treatment than in those who received best supportive care (7, 10). Nakamura et al. reported that of the 90 patients who underwent neoadjuvant chemotherapy followed by P/D, 57 (63.3%) developed recurrence. Total 43 patients (75.4%) underwent post-recurrence treatment that included ≥3 cycles of chemotherapy (n = 39), surgery (n = 3) and radiofrequency ablation (n = 1). The survival tie was significantly longer in patients who received post-recurrence treatment than in those who received best supportive care (median post-recurrence survival: 24.1 vs. 4.2 months) (7). Furthermore, the treatment of MPM after recurrence is important for achieving overall good outcomes. However, Both P/D and EPP are highly invasive surgeries, with poor PS in patients who have post-operative recurrence of MPM. Furthermore, in many cases, post-recurrence treatment is challenging because of lack of evidence (7). Historically, no therapeutic agent has demonstrated strong activity against post-recurrence MPM (11).

In order to solve this problem, in recent years, nivolumab has shown promising efficacy for MPM and has received considerable attention. Okada et al. reported the MERIT trial for the second- or third-line treatment of MPM. About 34 patients were enrolled in this study. There was an ORR of 29.4% and DCR of 67.6%. The median OS and PFS were 17.3 and 6.1 months, respectively (4). Scherppereel et al. reported MAPS2 trial for second- or third-line nivolumab vs. nivolumab plus ipilimumab in MPM. About 54 patients in the nivolumab group, ORR and 12-week DCR were achieved by 18.5 and 39.7%, respectively. The median OS and PFS were 11.9 and 4.0 months, respectively (12). In the current study, an ORR of 20.0% and a DCR of 77.1% were confirmed with central assessment using the mRECIST in patients with post-operative recurrence of MPM; these findings were in agreement with the results of MERIT and MAPS2. In sum, nivolumab could be effective for patients with post-operative recurrence of MPM. Thus far, only platinum-based combination treatment with pemetrexed was the established treatment for MPM, and there was no evidence that the second-line and after treatment is effective. Nivolumab is expected to become popular and be increasingly used in the treatment of patients with post-operative recurrence of MPM to improve OS in MPM patients.

Sarcomatoid or biphasic subtypes are reported to have poor prognosis. The reason was believed to be the ineffectiveness of platinum-based doublet chemotherapy (13). In the MERIT, in patients with sarcomatoid and biphasic subtypes, the ORR was 2 in 3 patients and 1 in 4 patients. This result suggested that nivolumab had a beneficial effect in patients with sarcomatoid and biphasic subtypes. In the current study, the histological subtypes were sarcomatoid in 1 patient and biphasic in 2 patients. The most frequent histological subtype was the epithelioid type (n = 32, 91.4%) because we performed multimodality treatment for epithelioid MPM, in principle. In the one patient with sarcomatoid subtype, the best radiological outcome was that of PD. However, it is noteworthy that although chest wall masses and intrapulmonary nodules attended to grow larger, adrenal metastasis was considerably reduced. The patient was administered nivolumab for a total of 11 cycles after PD. Eventually, the patient who received best supportive care was alive at 15 months after the initial administration of nivolumab. Of the 2 patients with biphasic subtype, the best radiological outcomes were SD in 1 patient and PD in 1 patient. Effects of histological subtypes on treatment efficacy remain to be evaluated.

With regard to recurrence, 22 patients (62.9%) developed local recurrence, 7 (20.0%) developed distant recurrence and 6 (17.1%) developed both local and distant recurrences. The DCR as per the recurrence pattern is as follows: 81.8% (18 of 22 patients), 71.4% (5 of 7 patients) and 66.7% (4 or 6 patients) for local, distant and both recurrences, respectively. DCR tended to be higher in the local-recurrence group. Therefore, timely diagnosis and early treatment are crucial for patients with recurrence.

In the current study, all the patients underwent multimodality treatment, including curative-intent surgery for MPM. Furthermore, most patients underwent post-recurrence treatment, including chemotherapy, surgery and radiotherapy before the administration of nivolumab. Most patients with post-operative recurrence of MPM have declined cardiopulmonary function and PS (2). Hence, the patients who underwent multiple treatments in the present study had an increased risk of AEs, such as pulmonary toxicity, bone marrow suppression and gastrointestinal toxicity. These certain specific AEs of nivolumab are thought to be triggered by an excessive immune reaction (14). In the current study, we examined AEs in 35 patients who were administered nivolumab. Total 39 AEs were detected in 28 patients (80.0%), with grade-3 AEs in 4 patients (11.4%). No grade-4 or grade-5 AEs were observed. In terms of safety, these events were not particularly problematic. Nivolumab administration had to be completely stopped in only 4 patients because of AEs, enabling the administration nivolumab with a median of 8 cycles. Total 47% and 14% patients experienced grade ≥3 AEs as per the MERIT and MAPS2, respectively (4, 12). The incidence of AEs was similar to that reported in these studies. Thus, these findings suggest that nivolumab provides a clinical benefit and safety and can therefore be considered as an option for treating patients with post-operative recurrence of MPM.

There are certain limitations of the present study. The retrospective single-center design involves a risk of bias, and the results should be interpreted with caution. The follow-up period after nivolumab administration was started was relatively short. In the current study, we evaluated the initial effect and feasibility of nivolumab administration; however, the prognostic factors, including PD-L1, were not investigated. Further research is necessary to examine the effectiveness of this drug on a larger sample size and a longer follow-up period.

Conclusions

In conclusion, nivolumab demonstrated promising efficacy and reasonable safety for patients with post-operative recurrence of MPM. Further studies are warranted to evaluate the long-term survival and prognostic factors of nivolumab for MPM.

Acknowledgements

The authors thank to Drs Yoshitomo Okumura, Teruhisa Takuwa, Akihiro Fukuda, Toshiyuki Minami, Ryo Takahashi, Koji Mikami, Eisuke Shibata, Maiko Niki, Yasuhiro Nakajima, Yoshiki Negi and Hirotoshi Ishigaki for their significant contribution to this study.

Abbreviations

 
• MPM

  malignant pleural mesothelioma

 
• P/D

  pleurectomy/decortication

 
• EPP

  extrapleural pneumonectomy

 
• PS

  performance status

 
• FDA

  Food and Drug Administration

 
• PD-1

  programmed death-1

 
• CT

  computed tomography

 
• mRECIST

  modified Response Evaluation Criteria in Solid Tumors

 
• FDG-PET

  fluorodeoxyglucose-positron emission tomography

 
• SD

  stable disease

 
• PD

  progressive disease

 
• PR

  partial response

 
• CR

  complete response

 
• ORR

  objective response rate

 
• DCR

  disease control rate

 
• OS

  overall survival

 
• PFS

  progression-free survival

 
• AEs

  adverse events

 
• CTCAE v5.0

  National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0

 
• PD-L1

  programmed death ligand 1