key: cord-0702760-z7bvb2ui
authors: Ikeda, Satoshi; Kato, Terufumi; Kenmotsu, Hirotsugu; Ogura, Takashi; Iwasawa, Shunichiro; Sato, Yuki; Harada, Toshiyuki; Kubota, Kaoru; Tokito, Takaaki; Okamoto, Isamu; Furuya, Naoki; Yokoyama, Toshihide; Hosokawa, Shinobu; Iwasawa, Tae; Yamanaka, Takeharu; Okamoto, Hiroaki
title: A phase II study of atezolizumab for pretreated non-small cell lung cancer with idiopathic interstitial pneumonias
date: 2020-08-25
journal: J Thorac Oncol
DOI: 10.1016/j.jtho.2020.08.018
sha: 2332c38904cc6f2d98f9059965667465586ab879
doc_id: 702760
cord_uid: z7bvb2ui

Abstract Introduction Interstitial pneumonia (IP) is one of the most common and poor prognostic comorbidities in patients with non-small cell lung cancer (NSCLC) and is also a known risk factor for pneumonitis. Atezolizumab monotherapy is an established treatment for recurrent NSCLC, and were reported to have a lower risk of pneumonitis than PD-1 inhibitors. This study aims to assess the safety and efficacy of atezolizumab monotherapy for pretreated advanced or recurrent NSCLC patients with idiopathic IP. Methods Advanced/recurrent NSCLC patients with comorbid idiopathic, chronic fibrotic IP with %forced vital capacity (FVC) of > 70% and no history of immune checkpoint inhibitors (ICIs) were enrolled. The patients received atezolizumab (1200 mg) every three weeks until the discontinuation criteria are met. The primary end point of this study is the one-year survival rate. A sample size of 38 patients was set. Results This study was terminated early due to high incidence of pneumonitis. Seventeen patients were enrolled, with a median age of 70 years. The median %FVC and %diffusing capacity for carbon monoxide at baseline were 85.4% and 54.4%, respectively. The incidence of pneumonitis was 29.4% (5/17) for all grade, 23.5% (4/17) for grade ≥ 3, and 5.9% (1/17) for grade 5. 57.1% (4/7) of patients with honeycomb lung developed grade ≥3 pneumonitis, whereas only one patient (10%) of grade 1 pneumonitis was found in patients without honeycomb lung (n=10). Conclusions NSCLC patients with comorbid IP as defined by the selection criteria for this study may have an increased risk of ICI-induced pneumonitis.

Interstitial pneumonia (IP) is one of the most common comorbidities with poor prognosis in patients with non-small cell lung cancer (NSCLC), with a prevalence of approximately 10%. 1 It is also a known risk factor for pneumonitis. [2] [3] Recently, two small single-arm trials of nivolumab, an anti-programmed cell death 1 (PD-1) antibody, demonstrated safety and promising efficacy in pretreated NSCLC patients with "mild" idiopathic IP, with an incidence of pneumonitis of 0% (n=6) 4 and 11.1% (n=18). 5 Based on these results, nivolumab was occasionally administered to NSCLC patients with IP in Japanese general practice.

Atezolizumab, an anti-programmed cell death-ligand 1 (PD-L1) antibody, is an established treatment for recurrent NSCLC. 6 In addition, the incidence of pneumonitis was reported to be lower than in previous reports of anti-PD-1 antibody and other cytotoxic agents. 7 Therefore, some have proposed that atezolizumab might be a safer option for second-line therapy among various immune checkpoint inhibitors (ICIs).

In this regard, we launched a multicenter, single arm phase II trial to assess the safety and efficacy of atezolizumab for patients with pretreated advanced or recurrent NSCLC with comorbid idiopathic IP. 8 However, this study was terminated early due to the high incidence of pneumonitis with Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3. We have determined that the information regarding the risks from this trial should be promptly made available to physicians using similar treatments in general practice and to physicians planning similar studies.

Patients who met the eligibility criteria (Supplemental Table 1 ) from 22 institutes in Japan were enrolled. As an eligibility criteria for IP, the following four items must be met; (1) high-resolution (HR) computed tomography (CT) revealing reticular shadow with basal and peripheral predominance suggestive of usual interstitial pneumonia (UIP) pattern, or peribronchovascular shadow suggestive of non-specific interstitial pneumonia pattern, (2) without known etiology (e.g., infection, pneumoconiosis, drug, sarcoidosis, and collagen vascular disease), (3) %forced vital capacity (FVC) ≥ 70%, and (4) %diffusing capacity for carbon monoxide (DLco) ≥ 35%. Ordinarily, histopathological examination and multidisciplinary discussion are recommended for the definitive diagnosis of IP. 9 However, considering the fact that the patients in this study are in a situation where treatment of advanced or recurrent NSCLC with poor prognosis is preferred over IP, and that few hospitals are able to perform histopathological examination and multidisciplinary discussion of IP satisfactorily, the diagnosis and pattern classification of IP in this study was based on HRCT findings.

Moreover, according to the post-marketing surveillance of pirfenidone and the subgroup analysis of the randomized phase III trial of nintedanib in patients with idiopathic pulmonary fibrosis, there is a particularly high risk of acute exacerbation in patients with a baseline FVC of < 70%. [10] [11] Based on these results, %FVC was set at ≥70% to ensure a certain level of safety in this study. 

The patients received atezolizumab (1200 mg for a day) every three weeks until the discontinuation criteria are met. The discontinuation criteria includes (1) disease progression, (2) occurrence of acute exacerbation of IP, and (3) occurrence of unacceptable immune-related adverse events, including pneumonitis, hepatotoxicity, hepatitis, nervous system disorder, renal disorder, eye disorder, and myocarditis with Common Terminology Criteria for Adverse Events (CTCAE) grade ≥3; colitis, diarrhea, pancreatitis, pan-hypopituitarism, and skin disorder with CTCAE grade ≥2; and encephalitis, meningitis, Guillain-Barre syndrome, and myasthenia gravis with CTCAE grade ≥1. 

The primary end point is the one-year survival rate. We set an expected value of 40% and a threshold value of 15%. Taking statistical points (two-sided α = 0.05; 1-β = 0.9) and ineligible patients into consideration, the sample size was set at 38 calculated by the exact binomial test.

Registration began on September 2, 2019. At the time of enrollment of 15 patients, 3 patients (20%) developed grade 3 pneumonitis, so the new patient enrollment was interrupted on January 31, 2020. Two patients from which consent had already been J o u r n a l P r e -p r o o f obtained were reintroduced, and a total of 17 patients were eventually registered.

Subsequently, one patient of pneumonitis worsened from grade 3 to 5, and one new patient developed grade 3 pneumonitis. Therefore, the present study was terminated following the recommendation of the efficacy and safety evaluation committee.

For the purposes of these reports focusing on adverse events, the data cutoff date was set to April 8, 2020. The median follow-up time was 2.95 months (95% confidence interval [CI]; 1.42-4.49). The seventeen patients enrolled in the trial who have received ≥ 1 cycle of treatment were categorized as the safety analysis population (Figure 1 ). In addition, we defined a Full Analysis Set (efficacy analysis population) as 16 patients, excluding one patient where the eligibility criteria were violated.

The characteristics of the 17 enrolled patients are summarized in Table 1 and Supplemental Table 2 . The median age was 70.0 years, and 16 patients (94.1%) were male. The median %FVC and %DLco at baseline were 85.4% and 54.4%, respectively.

The median delivered cycles of treatment to each patient was 3 ( Table 2 ). Five of the six patients, who were on treatment at the time the trial was terminated, continue to receive atezolizumab as a usual clinical treatment outside of this trial because the patients understood the risks and still wanted to (as of April 8, 2020).

Major adverse events are presented in Table 3 . The incidence of pneumonitis was 

We evaluated the risk factors for pneumonitis as a post-hoc analysis. The comparison of baseline characteristics between the patients who developed pneumonitis (n=5) and the patients without pneumonitis (n=12) revealed a significant lower body weight and hemoglobin and higher serum levels of C-reactive protein in patients with pneumonitis (Table 1 ). Subsequently, univariate logistic regression analysis did not identify statistically significant risk factor for pneumonitis, but suggested that honeycomb lung on HRCT may be a candidate risk factor (odds ratio 12.0, 95%CI, 0.936-154, p=0.056) ( Table 4 ). In fact, in seven patients with honeycomb lung on HRCT, four (57.1%) developed grade ≥ 3 pneumonitis (Figure 2 ). On the other hand, only one patient (10%) of grade 1 pneumonitis was found in patients without honeycomb lung (n=10).

As of April 8, 2020, when the data were cut off at this time, the primary endpoint, one-year survival rate, could not be assessed. The objective response rate and disease control rate were 6.3% and 62.5%, respectively. Median progression free survival time was 3.38 months (95% CI, 0.84-5.93).

The high incidence of pneumonitis indicated in the present study deviates from previously reported results of two prospective trials of nivolumab for pretreated NSCLC patients with IP. Since all these trials had small numbers of patients, it is possible that this difference was accidental. However, we supposed that the discrepancy in results may be due to two differences in eligibility criteria of IP between the trials: (1) acceptance or exclusion of patients with honeycomb lung, and (2) lower limit of % FVC.

Previous reported nivolumab trials excluded patients with a honeycomb lung, 4-5 but in this study, 41.1% (7/17) of patients had honeycomb lungs. In terms of pneumonitis or acute exacerbation of pre-existing IP induced by cytotoxic chemotherapy, honeycomb lung is one of the most common risk factors. 2 However, risk factors of ICI-induced pneumonitis in patients with comorbid IP remain unclear. Moreover, identifying honeycomb lung is difficult for non-specialists, and there is often disagreement about the identification of honeycomb lung, even among experienced chest radiologists. 12 Therefore, we did not include the presence of honeycomb lungs in the exclusion criteria for this study, in view of simplicity and generalization of the study results. However, risk factor analysis of pneumonitis in the present study showed the possibility that exclusion of patients with honeycomb lung on baseline CT images may reduce the risk of developing pneumonitis. Nonetheless, careful consideration of a larger number of patients is mandatory for the validation of this result.

Low FVC was also a common risk factor for cytotoxic-chemotherapy-induced pneumonitis or acute exacerbation of pre-existing IP. 13 Previously reported trials of nivolumab have included patients with %FVC ≥ 80%, whereas, this trial included a J o u r n a l P r e -p r o o f %FVC ≥ 70%. However, the median %FVC of our patients was 85.4%, and neither %FVC nor %DLco demonstrated a significant difference when compared with the presence or absence of pneumonitis. Since most of the patients enrolled in this study are smokers, the effect of emphysema may lead to an overestimation of FVC.

In the present situation where coronavirus disease 2019 (COVID-19) is rapidly spreading around the world, the additional difficulty of differentiating between ICI-induced pneumonitis and COVID-19-associated pneumonia can arise. Therefore, more prudence should be exercised when considering the administration of ICIs for NSCLC patients with IP.

As a limitation of this study, baseline imaging findings were assessed by a central review committee but were not completely blinded. Patients with known etiology of IP (e.g., infection, pneumoconiosis, drug, sarcoidosis, and collagen vascular disease) at present were excluded, but it cannot be ruled out that some of the enrolled patients had IP secondary to subclinical collagen vascular disease, which may have contributed to the high incidence of pneumonitis in this study. The frequency and severity of adverse events may change in the future due to the short observation period and the fact that some patients continue to receive atezolizumab outside of the study.

NSCLC patients with comorbid IP as defined by the selection criteria for this study may have an increased risk of ICI-induced pneumonitis. As the safety of ICIs for NSCLC with comorbid IP is still unclear, further safety data is warranted as a clinical trial in more carefully selected and larger number of patients. 

The epidemiology of interstitial lung disease and its association with lung cancer

The risk of cytotoxic chemotherapy-related exacerbation of interstitial lung disease with lung cancer

Summary of the Japanese Respiratory Society statement for the treatment of lung cancer with comorbid interstitial pneumonia

A pilot trial of nivolumab treatment for advanced non-small cell lung cancer patients with mild idiopathic interstitial pneumonia

Nivolumab for advanced non-small cell lung cancer patients with mild idiopathic interstitial pneumonia: A multicenter, open-label single-arm phase II trial

Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial

Incidence of Pneumonitis With Use of Programmed Death 1 and Programmed Death-Ligand 1 Inhibitors in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Trials

A phase II study of atezolizumab for pretreated advanced / recurrent non-small cell lung cancer with idiopathic interstitial pneumonias: rationale and design for the TORG1936 / AMBITIOUS study

All-case post-marketing surveillance of 1371 patients treated with pirfenidone for idiopathic pulmonary fibrosis

Efficacy of nintedanib in idiopathic pulmonary fibrosis across prespecified subgroups in INPULSIS

Interobserver variability in the CT assessment of honeycombing in the lungs

Low forced vital capacity predicts cytotoxic chemotherapy-associated acute exacerbation of interstitial lung disease in patients with lung cancer

Abbreviations: IP, interstitial pneumonia

HRCT, high-resolution computed tomography; UIP, usual interstitial pneumonia; NSIP, nonspecific interstitial pneumonia

DLco, diffusing capacity for carbon monoxide

Response Evaluation Criteria in Solid Tumors

Supplemental Table 2. Laboratory data at baseline

Continuous data are presented as medians

The p value was calculated by comparing subjects with and without pneumonitis

The authors would like to thank the patients, their families, Thoracic Oncology Research Group (TORG) data center staff, and all the investigators who participated in the TORG1936 / AMBITIOUS study.

The