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

The efficacy of nivolumab against metastatic non-small cell lung cancer (NSCLC) has been demonstrated; however, pneumonitis is relatively common and is a potentially life-threatening immune-related adverse event. Patients with idiopathic interstitial pneumonia (IIP) have a higher risk of pneumonitis and are generally excluded from clinical trials. Additionally, to date, a multicenter prospective trial for previously-treated NSCLC patients with IIP has not been performed. To fulfill this unmet medical need, we conducted a multicenter, open-label single-arm phase II trial to evaluate the efficacy and safety of nivolumab in NSCLC patients with mild IIP. Eligible patients had previously-treated, inoperable NSCLC with mild IIPs. Mild IIP was defined as a predicted vital capacity of at least 80% and possible usual interstitial pneumonia (UIP) or inconsistent with UIP pattern by chest high-resolution computed tomography. Primary end point was the 6 months PFS rate and secondary end point was the safety of this therapy. Eighteen patients were enrolled in this trial. Six months PFS rate was 56%, response rate was 39%, and disease control rate was 72%. There were no treatment-related deaths. One drug-related grade 3/4 nonhematologic event (grade 3 neurotoxicity) was observed. Two patients had grade 2 pneumonitis which improved by corticosteroid therapy. Nivolumab could be an effective therapy for NSCLC patients with mild IIPs.

Fujimoto D ，Yomota M ，Sekine A ，Morita M ，Morimoto T ，Hosomi Y ，Ogura T ，Tomioka H ，Tomii K ... -  《-》

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

Nivolumab has demonstrated efficacy against metastatic non-small cell lung cancer (NSCLC). However, immune-related adverse events can occur, among which pneumonitis is relatively common. Lung cancer patients with idiopathic interstitial pneumonia (IIP) have a higher risk of pneumonitis associated with anticancer therapy. We hypothesized that the benefit of nivolumab may outweigh the risks of pneumonitis in patients with NSCLC who have mild IIP. We performed a pilot trial to evaluate the safety of nivolumab in NSCLC patients with mild IIP. Previously treated, inoperable NSCLC patients with mild IIP were enrolled. Mild IIP was defined as having a predicted vital capacity ≥80% and a possible usual interstitial pneumonia (UIP) or inconsistent with UIP pattern on chest high-resolution computed tomography. Patients received nivolumab at a dose of 3mg/kg biweekly. Six patients were enrolled in this trial between April 2016 and December 2016. None experienced drug-related nonhematologic grade 3/4 or hematologic grade 4 adverse events in the 12 weeks following the initiation of nivolumab treatment. Furthermore, none of the patients had pneumonitis of any grade. At the time of analysis, all patients were alive, and 3 had experienced a partial response. Nivolumab therapy may be feasible in NSCLC patients with mild IIP. (Trial registration number: UMIN000022037).

Fujimoto D ，Morimoto T ，Ito J ，Sato Y ，Ito M ，Teraoka S ，Otsuka K ，Nagata K ，Nakagawa A ，Tomii K ... -  《-》

Three-year follow-up results from phase II studies of nivolumab in Japanese patients with previously treated advanced non-small cell lung cancer: Pooled analysis of ONO-4538-05 and ONO-4538-06 studies.

Nivolumab is a programmed cell death 1 (PD-1) receptor inhibitor antibody that enhances immune system antitumor activity. It is associated with longer overall survival (OS) than the standard treatment of docetaxel in patients with previously treated advanced squamous (SQ) and non-squamous (non-SQ) non-small cell lung cancer (NSCLC). We previously conducted two phase II studies of nivolumab in Japanese patients with SQ (ONO-4538-05) and non-SQ (ONO-4538-06) NSCLC, showing overall response rates (ORRs) (95% CI) of 25.7% (14.2-42.1) and 22.4% (14.5-32.9), respectively, with acceptable toxicity. In this analysis, we more precisely estimated the long-term safety and efficacy in patients with SQ and non-SQ NSCLC by pooling data from these two trials. SQ (N = 35) and non-SQ (N = 76) NSCLC patients received nivolumab (3 mg/kg, every 2 weeks) until progression or discontinuation. OS was estimated using the Kaplan-Meier method. A pooled analysis of SQ and non-SQ patients was also performed. In SQ NSCLC patients, the median OS (95% CI) was 16.3 months (12.4-25.2), and the estimated 1-year, 2-year, and 3-year survival rates were 71.4% (53.4-83.5), 37.1% (21.6-52.7), and 20.0% (8.8-34.4), respectively. In non-SQ NSCLC patients, median OS was 17.1 months (13.3-23.0), and the estimated 1-, 2-, and 3-year survival rates were 68.0% (56.2-77.3), 37.4% (26.5-48.1), and 31.9% (21.7-42.5), respectively. When SQ NSCLC and non-SQ NSCLC data were pooled, the median OS was 17.1 months (14.2-20.6), and the estimated 1-, 2-, and 3-year survival rates were 69.1% (59.6-76.8), 37.3% (28.3-46.2), and 28.1% (20.0-36.7), respectively. Twenty (76.9%) of 26 responders lived for 3 or more years. Nivolumab was well tolerated and no new safety signals were found. Treatment with nivolumab improved long-term survival and was well tolerated in patients with SQ and non-SQ NSCLC. JapicCTI-132072; JapicCTI-132073.

Horinouchi H ，Nishio M ，Hida T ，Nakagawa K ，Sakai H ，Nogami N ，Atagi S ，Takahashi T ，Saka H ，Takenoyama M ，Katakami N ，Tanaka H ，Takeda K ，Satouchi M ，Isobe H ，Maemondo M ，Goto K ，Hirashima T ，Minato K ，Sumiyoshi N ，Tamura T ... -  《Cancer Medicine》

Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: A multicenter retrospective cohort study.

Nivolumab has been shown to be effective and safe in previously treated patients with advanced non-small cell lung cancer (NSCLC). However, little is known regarding its performance in real-world (i.e., non-trial) settings. Furthermore, nivolumab efficacy is unknown in patients who are ineligible for clinical trials or who are categorized into small subgroups in such trials. We conducted a 15-center, observational, retrospective cohort study of patients with advanced NSCLC who received nivolumab monotherapy between January and December 2016. Of 613 patients included in our study, 141 had poor performance status (PS) and 106 were EGFR mutation - or ALK rearrangement-positive. The response and disease control rates were 20% and 44%, respectively; the estimated 1-year progression-free survival (PFS) was 18%. Multivariate analysis identified never smoking, poor PS, and EGFR mutation/ALK rearrangement as independent negative predictors of PFS. The most frequently reported grade ≥3 adverse event was pneumonitis (5% of patients). Severe pneumonitis (grade ≥3) occurred significantly earlier than mild pneumonitis (1.6 vs. 2.3 months, P = 0.031). Patients with pneumonitis achieved higher response rates and longer PFS than those without (37% vs. 18%, and 5.8 vs. 2.1 months, respectively; P = 0.002). Smoking status, PS, and EGFR mutation/ALK rearrangement were independent predictors of PFS. Our study elucidated nivolumab's efficacy in previously underreported patient populations; i.e., those with poor PS and/or with driver oncogenes. We also found that pneumonitis is not infrequent, and carries key implications for outcomes. These data should be useful for improving the clinical courses of nivolumab-treated patients with NSCLC.

Fujimoto D ，Yoshioka H ，Kataoka Y ，Morimoto T ，Kim YH ，Tomii K ，Ishida T ，Hirabayashi M ，Hara S ，Ishitoko M ，Fukuda Y ，Hwang MH ，Sakai N ，Fukui M ，Nakaji H ，Morita M ，Mio T ，Yasuda T ，Sugita T ，Hirai T ... -  《-》

High mortality and poor treatment efficacy of immune checkpoint inhibitors in patients with severe grade checkpoint inhibitor pneumonitis in non-small cell lung cancer.

The treatment efficacy of immune checkpoint inhibitor (ICI) and clinical outcomes in patients with non-small cell lung cancer (NSCLC) who develop severe grade checkpoint inhibitor pneumonitis (CIP) are unclear. Here, we report on the treatment efficacy of ICI and prognosis in NSCLC patients with severe grade CIP. In this retrospective cohort study, CIP severity, CIP-related mortality, and ICI efficacy in 71 patients with advanced NSCLC treated with ICIs were evaluated. Data was obtained from the patients' medical charts. All grade and severe grade CIP were observed in 22 and 11 patients, respectively. The CIP-related mortality rate was 22.7% (N = 5). An Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of ≥2 and pre-existing interstitial lung disease (ILD) were significantly associated with the development of severe grade CIP (P = 0.001 and P = 0.035, respectively). The median progression-free survival (PFS) and overall survival (OS) were significantly shorter in patients with severe grade CIP than in those without severe grade CIP (PFS 1.0 month, 95% confidence interval [CI] 0.5-2.0 vs. 3.5 months, 95% CI 2.0-5.0 months, P = 0.003; OS 3.0 months, 95% CI 0.5-13 vs. 12.7 months, 95% CI 8.0-21.0 months, P = 0.011). CIP is a serious complication with a poor prognosis associated with high mortality. The efficacy of ICI is significantly worse in patients with severe grade CIP than in those without severe grade CIP. Whether ICIs should be administered to patients with CIP risk factors, such as an ECOG PS score of ≥2 or pre-existing ILD, should be carefully assessed.

Tone M ，Izumo T ，Awano N ，Kuse N ，Inomata M ，Jo T ，Yoshimura H ，Minami J ，Takada K ，Miyamoto S ，Kunitoh H ... -  《-》