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IMPORTANCE Although treatment with first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) plus antiangiogenic inhibitor has shown promising efficacies in patients with EGFR-mutated lung adenocarcinoma, recent single-arm studies have suggested that osimertinib plus antiangiogenic inhibitor might not work synergistically. OBJECTIVE To explore the efficacy and safety of osimertinib plus bevacizumab compared with osimertinib alone in patients with lung adenocarcinoma with EGFR T790M mutation. DESIGN, SETTING, AND PARTICIPANTS Patients with advanced lung adenocarcinoma that progressed with prior EGFR-TKI treatment (other than third-generation TKI) and acquired EGFR T790M mutation were enrolled. This study comprises a lead-in part with 6 patients and a subsequent phase 2 part. In phase 2, patients were randomized to osimertinib plus bevacizumab or osimertinib alone in a 1:1 ratio. INTERVENTIONS The combination arm received oral osimertinib (80 mg, every day) plus intravenous bevacizumab (15 mg/kg, every 3 weeks) until progression or unacceptable toxic effects. The control arm received osimertinib monotherapy. MAIN OUTCOMES AND MEASURES The primary end point was progression-free survival (PFS) assessed by investigators. Secondary end points consisted of overall response rate, time to treatment failure, overall survival, and safety. RESULTS From August 2017 through September 2018, a total of 87 patients were registered (6 in the lead-in part and 81 in the phase 2 part [intention-to-treat population]). Among those randomized, the median (range) age was 68 (41-82) years; 33 (41%) were male; 37 (46%) had an Eastern Cooperative Oncology Group performance status of 0; and 21 (26%) had brain metastasis. Although the overall response rate was better with osimertinib plus bevacizumab than osimertinib alone (68% vs 54%), median PFS was not longer with osimertinib plus bevacizumab (9.4 months vs 13.5 months; adjusted hazard ratio, 1.44; 80% CI, 1.00 to 2.08; P = .20). Median time to treatment failure was also shorter in the combination arm vs the osimertinib arm (8.4 months vs 11.2 months; P = .12). Median overall survival was not different in the combination arm vs osimertinib arm (not reached vs 22.1 months; P = .96). In the combination arm, common adverse events of grade 3 or higher were proteinuria (n = 9; 23%), hypertension (n = 8; 20%). CONCLUSIONS AND RELEVANCE In this randomized clinical trial comparing osimertinib plus bevacizumab vs osimertinib alone, the combination arm failed to show prolongation of PFS in patients with advanced lung adenocarcinoma with EGFR T790M mutation.

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9506 Background: In NEJ026, a phase III trial comparing bevacizumab plus erlotinib (BE) to erlotinib monotherapy (E) for EGFR-mutated non-small-cell lung cancer (NSCLC), we demonstrated the progression-free survival (PFS) of BE was significantly superior to E (Saito et al. Lancet Oncol. 2019 May;20(5):625-635.). However overall survival analysis were immature at the cutoff date. Methods: Chemotherapy-naïve pts with advanced non-squamous NSCLC harboring EGFR-mutation were randomly assigned to receive either combination with erlotinib (150 mg daily) plus bevacizumab (15 mg/kg iv q3w) or erlotinib (150 mg daily). The primary endpoint was PFS. Secondary endpoints were OS, RR, safety, and QoL. Results: The 226 pts were assigned to BE (n=112) and E (n=114). For the follow-up OS analysis, the data cut-off date was 30 November 2019. Median follow up time was 39.2 months. Median OS was 50.7 months (95% CI, 37.3 months to not reached) with BE and 46.2 months (95% CI, 38.2 months to not reached) with E (hazard ratio, 1.00; 95% CI, 0.68 to 1.48). Twenty-nine patients (25.9%) in BE and twenty-six patients (23.2%) in E were treated by osimertinib as second line treatment. The median survival time between enrollment and progressive disease of second-line treatment (median PFS2) was 28.6 months (95% CI, 22.1 months to 35.9) with BE and 24.3 months (95% CI, 20.4 months to 29.1 months) with E (hazard ratio, 0.80; 95% CI, 0.59 to 1.10). In both arms, the median OS of patients with osimertinib second-line treatment were longer than other second-line chemotherapy groups [50.7 months (95% CI, 38.0 months to 50.7 months) vs 40.1 months (95% CI, 29.5 months to not reached), (hazard ratio, 0.645; 95% CI, 0.40 to 1.03), respectively. Conclusion: The additional effect of bevacizumab on erlotinib monotherapy for NSCLC with EGFR mutations gradually decreased in the order of PFS2 and survival, with no significant differences. Clinical trial information: UMIN000017069 .

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Purpose We evaluated the noninferiority of dexamethasone (DEX) on day 1, with sparing on days 2 and 3, combined with neurokinin-1 receptor antagonist (NK-RA) and palonosetron (Palo) compared with the 3-day use of DEX in highly-emetogenic chemotherapy (HEC). Patients and Methods Patients who were scheduled to receive HEC (cisplatin ≥ 50 mg/m or anthracycline plus cyclophosphamide) were randomly assigned to receive either DEX on days 1 to 3 (Arm D3) or DEX on day 1 and placebo on days 2 and 3 (Arm D1) combined with NK-RA and Palo. The primary end point was complete response (CR), defined as no emesis and no rescue medications during the overall (0 to 120 h) phase. The noninferiority margin was set at -15.0% (Arm D1 - Arm D3). Results A total of 396 patients-196 and 200 patients in Arms D3 and D1, respectively-were evaluated. CR rates during the overall period were 46.9% for Arm D3 and 44.0% for Arm D1 (95% CI, -12.6% to 6.8%; P = .007). CR rates during the acute (0 to 24 h) phase were 63.3% and 64.5% for Arms D3 and D1, respectively (95% CI, -8.1% to 10.6%; P < .001), and they were 56.6% and 51.5%, respectively, during the delayed (24 to 120 h) phase (95% CI, -14.8% to 4.6%; P = .023). Hot flushes and tremors were observed more frequently as DEX-related adverse events on days 4 and 5 in Arm D3, whereas anorexia, depression, and fatigue were observed more frequently on days 2 and 3 in Arm D1. As an indication of quality of life, global health status was similar in both arms. Conclusion Antiemetic DEX administration on days 2 and 3 can be spared when combined with NK-RA and Palo in HEC.

Introduction: Interstitial pneumonia (IP) is one of the most common and poor prognostic comorbidities in patients with NSCLC and a known risk factor for pneumonitis. Atezolizumab monotherapy is an established treatment for recurrent NSCLC and reported to have a lower risk of pneumonitis than programmed cell death protein 1 inhibitors. This study aimed to assess the safety and efficacy of atezolizumab monotherapy in patients with pretreated advanced or recurrent NSCLC with idiopathic IP. Methods: Patients with advanced or recurrent NSCLC with comorbid idiopathic, chronic fibrotic IP with % forced vital capacity of greater than 70% and no history of immune checkpoint inhibitors were enrolled. The patients received atezolizumab (1200 mg) every 3 weeks until the discontinuation criteria were met. The primary end point of this study was the 1-year survival rate. A sample size of 38 patients was set. Results: This study was terminated early owing to high incidence of pneumonitis. A total of 17 patients were enrolled, with a median age of 70 years. The median % forced vital capacity and % diffusing capacity for carbon monoxide at baseline were 85.4% and 54.4%, respectively. The incidence of pneumonitis was 29.4% (5 of 17) for all grades, 23.5% (4 of 17) for grade greater than or equal to 3, and 5.9% (1 of 17) for grade 5. A total of 57.1% patients (4 of 7) with honeycomb lung developed pneumonitis with a grade greater than or equal to 3, whereas only one patient (10%) without honeycomb lung (n ¼ 10) with grade 1 pneumonitis was found. Conclusions: Patients with NSCLC with comorbid IP as defined by the selection criteria for this study might have an increased risk of immune checkpoint inhibitor-induced pneumonitis.