with inoperable/recurrent EGFRm+ NSCLC received afatinib at the approved dose (20e50 mg/day) and were observed following treatment initiation for 52 weeks/until premature discontinuation. Data were included for all patients who received afatinib during the investigational period of this study, thus minimizing patient selection bias. The incidence/severity of adverse drug reactions (ADRs)/serious ADRs (sADRs) was the primary endpoint. Other endpoints included effectiveness (objective response rate [ORR]) and the incidence/severity of ADRs of special interest (diarrhea, rash/acne, nail effects [NEs] and interstitial lung disease [ILD]). Result: As of February 2017, 1,602 patients were included in the analysis (59% female, 81% aged <75 years, 86% ECOG PS 0e1, 83% BMI <25 kg/m 2). 97% of patients had adenocarcinoma, and 64%/26% had EGFR Del19/L858R mutations. 70% had 1 line of prior chemotherapy; 48%/30% had prior gefitinib/ erlotinib. Afatinib starting dose was 40 mg in 77% of patients. 95% had ADRs (36% grade 3). The most frequently reported ADRs (all grade/ grade 3e4) were diarrhea (78%/15%), rash/acne (59%/6%), stomatitis (31%/4%), and NEs (38%/4%). ILD (all grade/grade 3e4/grade 5) occurred in 4%/2%/1% of patients. Median (range) time to initial onset was 5.0 (1e316) days for diarrhea, 11.0 (1e406) days for rash/ acne, 9.0 (1e327) days for stomatitis, 38.0 (1e526) days for NEs, and 35.5 (3e329) days for ILD. Four patients (<1%) had creatinine elevation following grade 3 diarrhea. Dose reductions/permanent discontinuations occurred in 8%/7% of patients following diarrhea, 6%/4% following rash/acne, 3%/2% following stomatitis, 5%/2% following NEs, and <1%/4% following ILD. 33% of patients experienced sADRs. ADR frequency was associated with starting dose (96%/ 91% with 40/<40 mg afatinib), but was not unfavorably impacted by age, ECOG PS, number of prior chemotherapies, or previous EGFR TKIs. ORR with afatinib was higher in EGFR TKI-naïve patients than those who had previously been treated with EGFR TKIs (68% versus 21%). Conclusion: Consistent with previous studies, afatinib was effective in inoperable/recurrent EGFRm+ NSCLC, particularly as first-line targeted treatment (ORR w70%). ADRs were predictable and generally manageable. ADR frequency was not notably affected by age, ECOG PS or number of previous therapies. In clinical practice, patients should be closely monitored and ADRs, particularly diarrhea and ILD, treated early to prevent sADRs.

BackgroundAfatinib is approved for first-line treatment of patients with epidermal growth factor receptor mutation-positive (EGFRm+) non-small-cell lung cancer (NSCLC). Here, we report findings from a combined analysis of three phase IIIb studies of afatinib in EGFR tyrosine kinase inhibitor (TKI)-naïve patients.MethodsEGFR-TKI-naïve patients with EGFRm+ NSCLC received afatinib 40 mg/day. Dose reductions were permitted for adverse events (AEs). Efficacy endpoints included progression-free survival (PFS), time to symptomatic progression (TTSP), and tumor response. Subgroup analyses were performed by Eastern Cooperative Oncology Group performance status (ECOG PS), presence of brain metastasis, age and common/uncommon EGFR mutations (plus other factors).Results1108 patients were treated. Median age was 61 years (range, 25–89); 19.2% had baseline brain metastases, 4.4% had ECOG PS ≥2, and 17.9% had tumors harboring uncommon mutations. Treatment-related AEs (TRAEs) were reported in 97.2%, most commonly diarrhea and rash. 41.6% had AEs leading to dose reduction. Median PFS was 13.0 months [95% confidence interval (CI): 12.0–13.8]; median TTSP was 14.8 months (95% CI: 13.9–16.1). Objective response rate (ORR) was 55.0%. Age, presence of baseline brain metastases, major (G719X, L861Q, S768I) or compound uncommon mutations had little/no effect on PFS, TTSP, or ORR, while outcomes were poorer in patients with ECOG PS 2 or exon 20 insertion/T790M mutations.ConclusionsAfatinib was tolerable with no new safety signals. Afatinib demonstrated encouraging efficacy in a broad patient population, including those with brain metastases or uncommon EGFR mutations.

Background: Several genetically altered signaling pathways have been profiled in NSCLC, enabling advanced management of NSCLC using targeted therapies. This study investigated the therapeutic spectrum of NSCLC with uncommon molecular alterations by allocating patients to treatment arms based on molecular aberrations; targeted therapies alpelisib (PI3Kai), capmatinib (METi), ceritinib (ALKi), and binimetinib (MEKi) were evaluated. Method: The study was based on the umbrella design. Key objectives: investigate feasibility of using one trial for different agents based on biomarker-integrated analysis, assess antitumor activity, characterize safety, tolerability and PK profiles of individual agents. Key eligibility criteria: age 18 years; ECOG PS 2; failed prior treatment/unsuitable for chemotherapy. Documentation of locally determined molecular alterations before treatment allocation was required (alpelisib, 350 mg QD: PIK3CA mutation/amplification; capmatinib, 400 mg BID (tablet): MET IHC overexpression/amplification; ceritinib, 750 mg QD: ALK or ROS1 rearrangement; binimetinib, 45 mg BID: KRAS, NRAS or BRAF mutation). Result: Sixty-six patients with advNSCLC were enrolled (median age 58 years; 65.2% male: alpelisib, n¼2; capmatinib, n¼16; ceritinib, n¼26; binimetinib, n¼22). As of Feb 28, 2018, 10 patients in ceritinib and 2 in binimetinib arms were ongoing. Twenty-four patients had confirmed partial responses (36.4%): alpelisib, 0%; capmatinib, 18.8%; ceritinib, 73.1%; binimetinib, 9.1% (Figure). Longest mPFS (14.4 months) was in ceritinib arm. Among the most common treatment-related AEs: alpelisib: malaise, hyperglycemia, dysgeusia; capmatinib: nausea, anemia, peripheral edema, decreased appetite; ceritinib: diarrhea, vomiting, ALT/AST elevation; binimetinib: mouth ulceration, AST, blood CPK increased, rash. Most AEs were grade 1/2. Conclusion: Objective responses/tumor shrinkage were observed in the study; highest ORR and mPFS were observed with ceritinib, although patient numbers differed between arms. All treatments were well tolerated; no new safety signals were observed. This study demonstrated the feasibility of an umbrella trial and importance of precision medicine in the management of advNSCLC with uncommon molecular alterations.

PD-L1 inhibitors treatment is associated with impaired outcome in pts with advanced NSCLC pts. This reduction is independent of standard prognostic factors. Biological correlative analyses suggest a tumor immunosuppressed state in ACE inhibitor group. These results should be validated in larger prospective cohorts.

Background Afatinib has been shown as a suitable option for the treatment of epidermal growth factor receptor mutationpositive (EGFRm+) non-small-cell lung cancer (NSCLC) in randomized controlled trials. However, patients treated in realworld clinical practice, including elderly patients, and those with brain metastases or poor Eastern Cooperative Oncology Group (ECOG) performance statuses, are often excluded from these studies. Objective To report the final results, with a particular focus on patients enrolled in China, from a prospective phase IIIb, "near real-world" study of afatinib in tyrosine kinase inhibitor (TKI)-naïve Asian patients with EGFRm+ NSCLC. Patients and Methods NCT01953913 was conducted at 34 centers across Asia. Entry criteria were broad to reflect real-world settings. Patients received afatinib 40 mg/day until tumor progression, lack of clinical benefit, or poor tolerability. Assessments included safety, time to symptomatic progression (TTSP), and progression-free survival (PFS). Results 541 patients were treated, of whom 412 were enrolled in China. Dose reductions were implemented in 28.7% of patients overall, and 17.7% of patients from China. Safety findings were consistent with phase III studies of afatinib. Median TTSP in all patients was 14.0 months (95% CI 12.9-15.9), and median PFS was 12.1 months (95% CI 11.0-13.6). Median TTSP (13.8 months, 95% CI 12.7-16.1) and PFS (11.4 months, 95% CI 10.9-13.7) were similar in patients from China to the overall population. Among patients from China who had dose reductions, TTSP was numerically longer than in those who did not (16.4 vs. 13.8 months; P = 0.0703), while PFS was significantly longer (13.9 vs. 11.1 months; P = 0.0275). Among patients from China with brain metastases, TTSP was numerically shorter than in those without (11.0 vs. 14.4 months; P = 0.0869), whereas PFS was significantly shorter (9.2 vs. 12.9 months; P = 0.0075). Conclusions Safety data for afatinib when used in a "near real-world" setting in patients with EGFRm+ NSCLC was consistent with the known safety profile of afatinib. Supporting efficacy data of afatinib were provided in all patients, and in those enrolled in China. Tolerability-guided afatinib dose reduction allowed patients to remain on treatment and continue to experience clinical benefit. Trial Registration Number and Date of Registration NCT01953913 (1 October 2013).Hai-Yan Tu and Jifeng Feng contributed equally to the article.