Radiogenomic Models Using Machine Learning Techniques to Predict EGFR Mutations in Non-Small Cell Lung Cancer.

BACKGROUND: The purpose of this study was to build radiogenomics models from texture signatures derived from computed tomography (CT) and 18F-FDG PET-CT (FDG PET-CT) images of non-small cell lung cancer (NSCLC) with and without epidermal growth factor receptor (EGFR) mutations. METHODS: Fifty patients diagnosed with NSCLC between 2011 and 2015 and with known EGFR mutation status were retrospectively identified. Texture features extracted from pretreatment CT and FDG PET-CT images by manual contouring of the primary tumor were used to develop multivariate logistic regression (LR) models to predict EGFR mutations in exon 19 and exon 20. RESULTS: An LR model evaluating FDG PET-texture features was able to differentiate EGFR mutant from wild type with an area under the curve (AUC), sensitivity, specificity, and accuracy of 0.87, 0.76, 0.66, and 0.71, respectively. The model derived from CT texture features had an AUC, sensitivity, specificity, and accuracy of 0.83, 0.84, 0.73, and 0.78, respectively. FDG PET-texture features that could discriminate between mutations in EGFR exon 19 and 21 demonstrated AUC, sensitivity, specificity, and accuracy of 0.86, 0.84, 0.73, and 0.78, respectively. Based on CT texture features, the AUC, sensitivity, specificity, and accuracy were 0.75, 0.81, 0.69, and 0.75, respectively. CONCLUSION: Non-small cell lung cancer texture analysis using FGD-PET and CT images can identify tumors with mutations in EGFR. Imaging signatures could be valuable for pretreatment assessment and prognosis in precision therapy.

Amplifying Outcomes: Checkpoint Inhibitor Combinations in First-Line Non-Small Cell Lung Cancer.

PURPOSE: Lung cancer is one of the most common types of cancer, resulting in approximately 1.8 million deaths worldwide. Immunotherapy using checkpoint inhibitors has become standard of care in advanced non-small cell lung cancer (NSCLC), and there is increasing interest in further improving outcomes through combination with other therapeutics. This systematic review evaluates emerging phase III data on the efficacy and safety of checkpoint inhibitor combinations as first-line treatment for advanced NSCLC. MATERIALS AND METHODS: Published and presented literature was searched using the key search terms "non-small cell lung cancer" AND "checkpoint-inhibitors" (OR respective aliases) AND phase III trials. Seven randomized phase III clinical trials reporting outcomes on checkpoint inhibitor combinations in first-line advanced NSCLC were identified. RESULTS: Four first-line trials reported outcomes for checkpoint inhibitor combinations in nonsquamous NSCLC. Pembrolizumab-chemotherapy, atezolizumab-chemotherapy, and atezolizumab-bevacizumab-chemotherapy showed significantly improved overall survival compared with controls in patients with advanced nonsquamous epidermal growth factor receptor-negative (EGFR-)/ anaplastic lymphoma kinase gene (ALK)- NSCLC. Two trials reported outcomes for squamous NSCLC, with pembrolizumab-chemotherapy reporting significantly improved overall survival (OS) compared with chemotherapy. The combination of nivolumab-ipilimumab in all-comer histology failed to improve OS compared with histology appropriate chemotherapy in patients regardless of their tumor mutational burden status. Based on improved survival and safety, either pembrolizumab monotherapy or pembrolizumab-chemotherapy administered based on PD-L1 status and histology is a preferred treatment option. Outcomes for atezolizumab-bevacizumab-chemotherapy in EGFR+/ALK+ patients are promising and require further exploration. CONCLUSION: First-line checkpoint inhibitors added to standard therapies improve overall survival for nonsquamous EGFR-/ALK- and squamous advanced NSCLC. IMPLICATIONS FOR PRACTICE: Single-agent immune checkpoint inhibitors are now standard of care for advanced non-small cell lung cancer (NSCLC), and emerging data show that combining these agents with established chemotherapy further improves outcomes. The phase III KEYNOTE-189 and IMPower-130 trials showed significantly improved survival using this strategy for nonsquamous NSCLC, and the phase III KEYNOTE-407 trial showed similar results in squamous disease. Checkpoint inhibitor combinations are therefore an important new treatment option for first-line NSCLC. Programmed death ligand-1 expression may inform the use of checkpoint inhibitor combination therapy, and overall tumor mutation burden is also an emerging biomarker for this new treatment strategy.

Retrospective Assessment of a Serum Proteomic Test in a Phase III Study Comparing Erlotinib plus Placebo with Erlotinib plus Tivantinib (MARQUEE) in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer.

BACKGROUND: The VeriStrat test provides accurate predictions of outcomes in all lines of therapy for patients with non-small cell lung cancer (NSCLC). We investigated the predictive and prognostic role of VeriStrat in patients enrolled on the MARQUEE phase III trial of tivantinib plus erlotinib (T+E) versus placebo plus erlotinib (P+E) in previously treated patients with advanced NSCLC. METHODS: Pretreatment plasma samples were available for 996 patients and were analyzed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry to generate VeriStrat labels (good, VS-G, or poor, VS-P). RESULTS: Overall, no significant benefit in overall survival (OS) and progression-free survival (PFS) were observed for the addition of tivantinib to erlotinib. Regardless of treatment arm, patients who were classified as VS-G had significantly longer PFS (3.8 mo for T+E arm, 2.0 mo for P+E arm) and OS (11.6 mo for T+E, 10.2 mo for P+E arm) than patients classified as VS-P (PFS: 1.9 mo for both arms, hazard ratio [HR], 0.584; 95% confidence interval [CI], 0.468-0.733; p < .0001 for T+E, HR, 0.686; 95% CI, 0.546-0.870; p = .0015 for P+E; OS: 4.0 mo for both arms, HR, 0.333; 95% CI, 0.264-0.422; p < .0001 for T+E; HR, 0.449; 95% CI, 0.353-0.576; p < .0001 for P+E). The VS-G population had higher OS than the VS-P population within Eastern Cooperative Oncology Group (ECOG) performance score (PS) categories. VS-G patients on the T+E arm had longer PFS, but not OS, than VS-G patients on the P+E arm (p = .0108). Among EGFR mutation-positive patients, those with VS-G status had a median OS more than twice that of any other group (OS: 31.6 mo for T+E and 22.8 mo for P+E), whereas VS-P patients had similar survival rates as VS-G, EGFR-wild type patients (OS: 13.7 mo for T+E and 6.5 mo for P+E). CONCLUSION: In these analyses, VeriStrat showed a prognostic role within EGOC PS categories and regardless of treatment arm and EGFR status, suggesting that VeriStrat could be used to identify EGFR mutation-positive patients who will have a poor response to EGFR tyrosine kinase inhibitors. IMPLICATIONS FOR PRACTICE: This study suggests that VeriStrat testing could enhance the prognostic role of performance status and smoking status and replicates findings from other trials that showed that the VeriStrat test identifies EGFR mutation-positive patients likely to have a poor response to EGFR tyrosine kinase inhibitors (TKIs). Although these findings should be confirmed in other populations, VeriStrat use could be considered in EGFR mutation-positive patients as an additional prognostic tool, and these results suggest that EGFR mutation-positive patients with VeriStrat "poor" classification could benefit from other therapeutic agents given in conjunction with TKI monotherapy.

EGFR mutation detection in circulating cell-free DNA of lung adenocarcinoma patients: analysis of LUX-Lung 3 and 6.

BACKGROUND: In the Phase III LUX-Lung 3/6 (LL3/LL6) trials in epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma patients, we evaluated feasibility of EGFR mutation detection using circulating cell-free DNA (cfDNA) and prognostic and predictive utility of cfDNA positivity (cfDNA+). METHODS: Paired tumour and blood samples were prospectively collected from randomised patients. Mutations were detected using cfDNA from serum (LL3) or plasma (LL6) by a validated allele-specific quantitative real-time PCR kit. RESULTS: EGFR mutation detection rates in cfDNA were 28.6% (serum) and 60.5% (plasma). Mutation detection in blood was associated with advanced disease characteristics, including higher performance score, number of metastatic sites and bone/liver metastases, and poorer prognosis. In patients with common EGFR mutations, afatinib improved progression-free survival vs chemotherapy in cfDNA+ (LL3: HR, 0.35; P=0.0009; LL6: HR, 0.25; P<0.0001) and cfDNA- (LL3: HR, 0.46; P<0.0001; LL6: HR, 0.12; P<0.0001) cohorts. A trend towards overall survival benefit with afatinib was observed in cfDNA+ patients. CONCLUSIONS: Plasma cfDNA is a promising alternative to biopsy for EGFR testing. Detectable mutation in blood was associated with more advanced disease and poorer prognosis. Afatinib improved outcomes in EGFR mutation-positive patients regardless of blood mutation status.

Perspectives in immunotherapy: meeting report from the "Immunotherapy Bridge", Napoli, November 30th 2016.

The complex interactions between the immune system and tumors lead the identification of key molecules that govern these interactions: immunotherapeutics were designed to overcome the mechanisms broken by tumors to evade immune destruction. After the substantial advances in melanoma, immunotherapy currently includes many other type of cancers, but the melanoma lesson is essential to progress in other type of cancers, since immunotherapy is potentially improving clinical outcome in various solid and haematologic malignancies. Monotherapy in pre-treated NSCLC is studied and the use of nivolumab, pembrolizumab and atezolizumab as second-line of advanced NSCLC is demonstrated as well as first line monotherapy and combination therapy in metastatic NSCLC studied. Patients with HNSCC have immunotherapeutic promises as well: the FDA recently approved moAbs targeting immune checkpoint receptors. Nivolumab in combination with ipilumumab showed acceptable safety and encouraging antitumor activity in metastatic renal carcinoma. HCCs have significant amounts of genomic heterogeneity and multiple oncogenic pathways can be activated: the best therapeutic targets identification is ongoing. The treatment of advanced/relapsed EOC remain clearly an unmet need: a better understanding of the relevant immuno-oncologic pathways and their corresponding biomarkers are required. UC is an immunotherapy-responsive disease: after atezolizumab, three other PD-L1/PD-L1 inhibitors (nivolumab, durvalumab, and avelumab) were approved for treatment of platinum-refractory metastatic urothelial carcinoma. Anti-PD-1/PD-L1 monotherapy is associated with a modest response rate in metastatic breast cancer; the addition of chemotherapy is associated with higher response rates. Immunotherapy safety profile is advantageous, although, in contrast to conventional chemotherapy: boosting the immune system leads to a unique constellation of inflammatory toxicities known as immune-related Adverse Events (irAEs) that may warrant the discontinuation of therapy and/or the administration of immunosuppressive agents. Research should explore better combination with less side effects, the right duration of treatments, combination or sequencing treatments with target therapies. At present, treatment decision is based on patient's characteristics.

Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial.

BACKGROUND: The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting. METHODS: This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660. FINDINGS: Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3-33·9). Progression-free survival (median 11·0 months [95% CI 10·6-12·9] with afatinib vs 10·9 months [9·1-11·5] with gefitinib; hazard ratio [HR] 0·73 [95% CI 0·57-0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95% CI 11·9-15·0] with afatinib vs 11·5 months [10·1-13·1] with gefitinib; HR 0·73 [95% CI 0·58-0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure. INTERPRETATION: Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population. FUNDING: Boehringer Ingelheim.

Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.

BACKGROUND: In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown. METHODS: We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. RESULTS: The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy. CONCLUSIONS: Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893.).

Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials.

BACKGROUND: We aimed to assess the effect of afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from two open-label, randomised, phase 3 trials. METHODS: Previously untreated patients with EGFR mutation-positive stage IIIB or IV lung adenocarcinoma were enrolled in LUX-Lung 3 (n=345) and LUX-Lung 6 (n=364). These patients were randomly assigned in a 2:1 ratio to receive afatinib or chemotherapy (pemetrexed-cisplatin [LUX-Lung 3] or gemcitabine-cisplatin [LUX-Lung 6]), stratified by EGFR mutation (exon 19 deletion [del19], Leu858Arg, or other) and ethnic origin (LUX-Lung 3 only). We planned analyses of mature overall survival data in the intention-to-treat population after 209 (LUX-Lung 3) and 237 (LUX-Lung 6) deaths. These ongoing studies are registered with ClinicalTrials.gov, numbers NCT00949650 and NCT01121393. FINDINGS: Median follow-up in LUX-Lung 3 was 41 months (IQR 35-44); 213 (62%) of 345 patients had died. Median follow-up in LUX-Lung 6 was 33 months (IQR 31-37); 246 (68%) of 364 patients had died. In LUX-Lung 3, median overall survival was 28.2 months (95% CI 24.6-33.6) in the afatinib group and 28.2 months (20.7-33.2) in the pemetrexed-cisplatin group (HR 0.88, 95% CI 0.66-1.17, p=0.39). In LUX-Lung 6, median overall survival was 23.1 months (95% CI 20.4-27.3) in the afatinib group and 23.5 months (18.0-25.6) in the gemcitabine-cisplatin group (HR 0.93, 95% CI 0.72-1.22, p=0.61). However, in preplanned analyses, overall survival was significantly longer for patients with del19-positive tumours in the afatinib group than in the chemotherapy group in both trials: in LUX-Lung 3, median overall survival was 33.3 months (95% CI 26.8-41.5) in the afatinib group versus 21.1 months (16.3-30.7) in the chemotherapy group (HR 0.54, 95% CI 0.36-0.79, p=0.0015); in LUX-Lung 6, it was 31.4 months (95% CI 24.2-35.3) versus 18.4 months (14.6-25.6), respectively (HR 0.64, 95% CI 0.44-0.94, p=0.023). By contrast, there were no significant differences by treatment group for patients with EGFR Leu858Arg-positive tumours in either trial: in LUX-Lung 3, median overall survival was 27.6 months (19.8-41.7) in the afatinib group versus 40.3 months (24.3-not estimable) in the chemotherapy group (HR 1.30, 95% CI 0.80-2.11, p=0.29); in LUX-Lung 6, it was 19.6 months (95% CI 17.0-22.1) versus 24.3 months (19.0-27.0), respectively (HR 1.22, 95% CI 0.81-1.83, p=0.34). In both trials, the most common afatinib-related grade 3-4 adverse events were rash or acne (37 [16%] of 229 patients in LUX-Lung 3 and 35 [15%] of 239 patients in LUX-Lung 6), diarrhoea (33 [14%] and 13 [5%]), paronychia (26 [11%] in LUX-Lung 3 only), and stomatitis or mucositis (13 [5%] in LUX-Lung 6 only). In LUX-Lung 3, neutropenia (20 [18%] of 111 patients), fatigue (14 [13%]) and leucopenia (nine [8%]) were the most common chemotherapy-related grade 3-4 adverse events, while in LUX-Lung 6, the most common chemotherapy-related grade 3-4 adverse events were neutropenia (30 [27%] of 113 patients), vomiting (22 [19%]), and leucopenia (17 [15%]). INTERPRETATION: Although afatinib did not improve overall survival in the whole population of either trial, overall survival was improved with the drug for patients with del19 EGFR mutations. The absence of an effect in patients with Leu858Arg EGFR mutations suggests that EGFR del19-positive disease might be distinct from Leu858Arg-positive disease and that these subgroups should be analysed separately in future trials. FUNDING: Boehringer Ingelheim.

Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors.

PURPOSE: Bone complications of metastatic disease, including skeletal-related events (SREs), impair patients' functioning and quality of life. In a randomized, phase 3 trial of 1,776 patients with metastases from solid tumors (except breast or prostate) or multiple myeloma, denosumab was non-inferior to zoledronic acid (ZA) in delaying or preventing SREs. This ad hoc analysis reports outcomes in the subgroup of 1,597 patients with solid tumors, excluding patients with multiple myeloma. METHODS: Patients received monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg, adjusted for creatinine clearance, with calcium and vitamin D supplementation recommended. Endpoints included times to first on-study SRE, first-and-subsequent SREs, and pain worsening. RESULTS: Denosumab significantly delayed time to first on-study SRE compared with ZA (HR, 0.81; 95 % CI, 0.68-0.96) and time to first-and-subsequent SREs (RR, 0.85; 95 % CI, 0.72-1.00). Denosumab also significantly delayed time to development of moderate or severe pain (HR, 0.81; 95 % CI, 0.66-1.00), pain worsening (HR, 0.83; 95 % CI, 0.71-0.97), and worsening pain interference in patients with no/mild baseline pain (HR, 0.77; 95 % CI, 0.61-0.96). Adverse event rates were 96 % in both groups. Grade 3 or 4 hypocalcemia, mostly without clinical sequelae, was more frequent in denosumab-treated patients (denosumab 4 %, ZA 2 %). Osteonecrosis of the jaw occurred infrequently (denosumab 0.8 %, ZA 1.1 %). CONCLUSIONS: Denosumab was more effective in delaying or preventing SREs in patients with bone metastases from solid tumors and also prevented pain progression compared to ZA in this ad hoc analysis.

Transitioning to Neoadjuvant Therapy for Resectable Non-Small Cell Lung Cancer: Trends and Surgical Outcomes in a Regionalized Pulmonary Oncology Network.

BACKGROUND: Several regulatory agencies have approved the use of the neoadjuvant chemo-immunotherapy for resectable stage II and III of non-small cell lung cancer (NSCLC) and numerous trials investigating novel agents are underway. However, significant concerns exist around the feasibility and safety of offering curative surgery to patients treated within such pathways. The goal in this study was to evaluate the impact of a transition towards a large-scale neoadjuvant therapy program for NSCLC. METHODS: Medical charts of patients with clinical stage II and III NSCLC who underwent resection from January 2015 to December 2020 were reviewed. The primary outcome was perioperative complication rate between neoadjuvant-treated versus upfront surgery patients. Multivariable logistic regression estimated occurrence of postoperative complications and overall survival was assessed as an exploratory secondary outcome by Kaplan-Meier and Cox-regression analyses. RESULTS: Of the 428 patients included, 106 (24.8%) received neoadjuvant therapy and 322 (75.2%) upfront surgery. Frequency of minor and major postoperative complications was similar between groups (P = .22). Occurrence in postoperative complication was similar in both cohort (aOR = 1.31, 95% CI 0.73-2.34). Neoadjuvant therapy administration increased from 10% to 45% with a rise in targeted and immuno-therapies over time, accompanied by a reduced rate of preoperative radiation therapy use. 1-, 2-, and 5-year overall survival was higher in neoadjuvant therapy compared to upfront surgery patients (Log-Rank P = .017). CONCLUSIONS: No significant differences in perioperative outcomes and survival were observed in resectable NSCLC patients treated by neoadjuvant therapy versus upfront surgery. Transition to neoadjuvant therapy among resectable NSCLC patients is safe and feasible from a surgical perspective.

Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial.

BACKGROUND: Afatinib, an irreversible ErbB-family blocker, has shown preclinical activity when tested in EGFR mutant models with mutations that confer resistance to EGFR tyrosine-kinase inhibitors. We aimed to assess its efficacy in patients with advanced lung adenocarcinoma with previous treatment failure on EGFR tyrosine-kinase inhibitors. METHODS: In this phase 2b/3 trial, we enrolled patients with stage IIIB or IV adenocarcinoma and an Eastern Cooperative Oncology Group performance (ECOG) performance score of 0-2 who had received one or two previous chemotherapy regimens and had disease progression after at least 12 weeks of treatment with erlotinib or gefitinib. We used a computer-generated sequence to randomly allocate patients (2:1) to either afatinib (50 mg per day) or placebo; all patients received best supportive care. Randomisation was done in blocks of three and was stratified by sex and baseline ECOG performance status (0-1 vs 2). Investigators, patients, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival (from date of randomisation to death), analysed on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00656136. FINDINGS: Between May 26, 2008, and Sept 21, 2009, we identified 697 patients, 585 of whom were randomly allocated to treatment (390 to afatinib, 195 to placebo). Median overall survival was 10·8 months (95% CI 10·0-12·0) in the afatinib group and 12·0 months (10·2-14·3) in the placebo group (hazard ratio 1·08, 95% CI 0·86-1·35; p=0·74). Median progression-free survival was longer in the afatinib group (3·3 months, 95% CI 2·79-4·40) than it was in the placebo group (1·1 months, 0·95-1·68; hazard ratio 0·38, 95% CI 0·31-0·48; p<0·0001). No complete responses to treatment were noted; 29 (7%) patients had a partial response in the afatinib group, as did one patient in the placebo group. Subsequent cancer treatment was given to 257 (68%) patients in the afatinib group and 153 (79%) patients in the placebo group. The most common adverse events in the afatinib group were diarrhoea (339 [87%] of 390 patients; 66 [17%] were grade 3) and rash or acne (305 [78%] patients; 56 [14%] were grade 3). These events occurred less often in the placebo group (18 [9%] of 195 patients had diarrhoea; 31 [16%] had rash or acne), all being grade 1 or 2. Drug-related serious adverse events occurred in 39 (10%) patients in the afatinib group and one (<1%) patient in the placebo group. We recorded two possibly treatment-related deaths in the afatinib group. INTERPRETATION: Although we recorded no benefit in terms of overall survival with afatinib (which might have been affected by cancer treatments given after progression in both groups), our findings for progression-free survival and response to treatment suggest that afatinib could be of some benefit to patients with advanced lung adenocarcinoma who have failed at least 12 weeks of previous EGFR tyrosine-kinase inhibitor treatment. FUNDING: Boehringer Ingelheim Inc.

Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations.

PURPOSE: The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS). PATIENTS AND METHODS: In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs). RESULTS: A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio [HR], 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatment-related adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain. CONCLUSION: Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.

Bisphosphonates: prevention of bone metastases in lung cancer.

In patients with lung cancer, bone is one of the most frequent sites of distant spread, with approximately 30% of patients developing skeletal metastases. About half of these patients will experience a skeletal-related event, the occurrence of which not only affects quality of life, but is also associated with poor prognosis. Bisphosphonates are currently the mainstay for treating bone metastases in patients with lung cancer, with proven beneficial effects on prevention and delay of skeletal complications. Their role in preventing the development of skeletal metastases, their anti-tumoral properties and their effect on survival remain to be elucidated. Other bone-targeted therapies are being investigated in phase II and III clinical trials and might expand the therapeutic arsenal in the near future.

Afatinib (BIBW 2992) development in non-small-cell lung cancer.

Afatinib (BIBW 2992), a novel aniline-quinazoline derivative, irreversibly and equipotently targets the intrinsic kinase activity of all active ErbB receptor family members. Preclinical results show that afatinib is effective in lung cancer models, including those with EGF receptor (EGFR) mutations resistant to reversible first-generation EGFR inhibitors. Afatinib is being investigated in the LUX-Lung program, which will evaluate afatinib as a first-line treatment in patients with EGFR-activating mutations (LUX-Lung 2, 3 and 6) and as a second- or third-line treatment in patients that have acquired resistance to gefitinib and/or erlotinib (LUX-Lung 1, 4 and 5). LUX-Lung 1 and 2 have demonstrated, within their respective target groups, a significant increase in the disease control rate of 58 and 86%, respectively, and significant prolongation of progression-free survival. Further Phase III clinical trials are currently ongoing to assess afatinib in combination with paclitaxel (LUX-Lung 5), and compared with cisplatin/pemetrexed (LUX-Lung 3) or cisplatin/gemcitabine (LUX-Lung 6).

Optimal sequencing strategies in the treatment of EGFR mutation-positive non-small cell lung cancer: Clinical benefits and cost-effectiveness.

PURPOSE: To summarize current understanding of the efficacy, role, and cost-effectiveness of the available epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), and to evaluate sequencing strategies based on the available evidence. Summary. EGFR TKIs are the current standard of care for patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). Five EGFR TKIs are currently approved in the United States for use in a first-line setting; these TKIs differ in mechanism of action, efficacy, safety, and cost. Most patients develop resistance to first-line EGFR TKIs and require subsequent therapy with additional EGFR TKIs, chemotherapy, and/or other targeted agents. A major consideration when selecting EGFR TKIs, both as first-line or subsequent treatment options, is cost-effectiveness. Although clinical trials have shown that the second- and third-generation EGFR TKIs are superior in efficacy to the first-generation agents, pharmacoeconomic studies suggest that the first-generation agents are the most cost-effective, with the second-generation TKI afatinib also considered cost-effective in some studies. Despite its impressive efficacy, osimertinib appears to be less cost-effective due to substantially higher acquisition costs. CONCLUSION: Preliminary data suggest that first-line afatinib followed by osimertinib may offer promising survival outcomes and, on the basis of efficacy alone, may represent an optimal sequencing strategy in the majority of patients with EGFR mutation-positive NSCLC, in particular Asian patients and those with Del19-positive tumors. However, considerably more research into outcomes and costs associated with consecutive sequencing of EGFR TKIs is needed before any conclusions can be reached.

A Randomized, Double-Blind, Placebo-Controlled, Phase III Noninferiority Study of the Long-Term Safety and Efficacy of Darbepoetin Alfa for Chemotherapy-Induced Anemia in Patients With Advanced NSCLC.

INTRODUCTION: This study evaluated noninferiority of darbepoetin alfa versus placebo for overall survival (OS) and progression-free survival (PFS) in anemic patients with NSCLC treated to a 12.0-g/dL hemoglobin (Hb) ceiling. METHODS: Adults with stage IV NSCLC expected to receive two or more cycles of myelosuppressive chemotherapy and Hb less than or equal to 11.0 g/dL were randomized 2:1 to blinded 500 µg darbepoetin alfa or placebo every 3 weeks. The primary endpoint was OS; a stratified Cox proportional hazards model was used to evaluate noninferiority (upper confidence limit for hazard ratio [HR] < 1.15). Secondary endpoints were PFS and incidence of transfusions or Hb less than or equal to 8.0 g/dL from week 5 to end of the efficacy treatment period. RESULTS: The primary analysis set included 2516 patients: 1680 were randomized to darbepoetin alfa; 836 to placebo. The study was stopped early per independent Data Monitoring Committee recommendation after the primary endpoint was met with no new safety concerns. Darbepoetin alfa was noninferior to placebo for OS (stratified HR = 0.92; 95% confidence interval [CI]: 0.83‒1.01) and PFS (stratified HR = 0.95; 95% CI: 0.87‒1.04). Darbepoetin alfa was superior to placebo for transfusion or Hb less than or equal to 8.0 g/dL from week 5 to end of the efficacy treatment period (stratified odds ratio = 0.70; 95% CI: 0.57‒0.86; p < 0.001). Objective tumor response was similar between the groups (darbepoetin alfa, 36.4%; placebo, 32.6%). Incidence of serious adverse events was 31.1% in both groups. No unexpected adverse events were observed. CONCLUSIONS: Darbepoetin alfa dosed to a 12.0-g/dL Hb ceiling was noninferior to placebo for OS and PFS and significantly reduced odds of transfusion or Hb less than or equal to 8.0 g/dL in anemic patients with NSCLC receiving myelosuppressive chemotherapy.

Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial.

BACKGROUND: Two phase II trials in patients with previously-treated advanced non-small-cell lung cancer suggested that gefitinib was efficacious and less toxic than was chemotherapy. We compared gefitinib with docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer who had been pretreated with platinum-based chemotherapy. METHODS: We undertook an open-label phase III study with recruitment between March 1, 2004, and Feb 17, 2006, at 149 centres in 24 countries. 1466 patients with pretreated (>/=one platinum-based regimen) advanced non-small-cell lung cancer were randomly assigned with dynamic balancing to receive gefitinib (250 mg per day orally; n=733) or docetaxel (75 mg/m(2) intravenously in 1-h infusion every 3 weeks; n=733). The primary objective was to compare overall survival between the groups with co-primary analyses to assess non-inferiority in the overall per-protocol population and superiority in patients with high epidermal growth factor receptor (EGFR)-gene-copy number in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00076388. FINDINGS: 1433 patients were analysed per protocol (723 in gefitinib group and 710 in docetaxel group). Non-inferiority of gefitinib compared with docetaxel was confirmed for overall survival (593 vs 576 events; hazard ratio [HR] 1.020, 96% CI 0.905-1.150, meeting the predefined non-inferiority criterion; median survival 7.6 vs 8.0 months). Superiority of gefitinib in patients with high EGFR-gene-copy number (85 vs 89 patients) was not proven (72 vs 71 events; HR 1.09, 95% CI 0.78-1.51; p=0.62; median survival 8.4 vs 7.5 months). In the gefitinib group, the most common adverse events were rash or acne (360 [49%] vs 73 [10%]) and diarrhoea (255 [35%] vs 177 [25%]); whereas in the docetaxel group, neutropenia (35 [5%] vs 514 [74%]), asthenic disorders (182 [25%] vs 334 [47%]), and alopecia (23 [3%] vs 254 [36%]) were most common. INTERPRETATION: INTEREST established non-inferior survival of gefitinib compared with docetaxel, suggesting that gefitinib is a valid treatment for pretreated patients with advanced non-small-cell lung cancer.

First-line afatinib for advanced EGFRm+ NSCLC: Analysis of long-term responders in the LUX-Lung 3, 6, and 7 trials.

OBJECTIVES: In patients with advanced epidermal growth factor receptor mutation-positive (EGFRm+) non-small cell lung cancer (NSCLC), first-line afatinib significantly improved progression-free survival (PFS) and objective response vs. platinum-doublet chemotherapy in the phase III LUX-Lung 3 and LUX-Lung 6 trials, and significantly improved PFS, time to treatment failure and objective response vs. gefitinib in the phase IIb LUX-Lung 7 trial. We report post-hoc analyses of efficacy, safety and patient-reported outcomes (PROs) in afatinib long-term responders (LTRs) in these trials. METHODS: Treatment-naïve patients with stage IIIB/IV EGFRm + NSCLC randomized to afatinib in LUX-Lung 3/LUX-Lung 6/LUX-Lung 7 were included in the analysis. Patients treated with afatinib for ≥ 3 years were defined as LTRs. RESULTS: In LUX-Lung 3, LUX-Lung 6, and LUX-Lung 7, 24/229 (10%), 23/239 (10%) and 19/160 (12%) afatinib-treated patients were LTRs. Baseline characteristics were similar to the study populations, except for the proportions of women (LUX-Lung 3/LUX-Lung 6 only; 92/78% vs. 64% overall) and Del19-positive patients (63-79% vs. 49-58% overall). Median treatment duration among LTRs was 50, 56 and 42 months, and median PFS was 49.5, 55.5, and 42.2 months in LUX-Lung 3/LUX-Lung 6/LUX-Lung 7, respectively. Median overall survival could not be estimated. Frequency of afatinib dose reduction was consistent with the LUX-Lung 3/LUX-Lung 6/LUX-Lung 7 overall populations. PROs were stable in LTRs, with slight improvements after 3 years of afatinib treatment vs. baseline scores. CONCLUSIONS: In the LUX-Lung 3/LUX-Lung 6/LUX-Lung 7 trials, 10-12% of afatinib-treated patients were LTRs. Long-term afatinib treatment was independent of tolerability-guided dose adjustment and had no detrimental impact on safety or PROs.

First-line afatinib vs gefitinib for patients with EGFR mutation-positive NSCLC (LUX-Lung 7): impact of afatinib dose adjustment and analysis of mode of initial progression for patients who continued treatment beyond progression.

PURPOSE: In the randomized phase IIb LUX-Lung 7 trial, afatinib significantly improved progression-free survival (PFS) and time-to-treatment failure vs gefitinib in patients with treatment-naïve epidermal growth factor receptor mutation-positive non-small cell lung cancer. We report post hoc analyses of tolerability-guided dose adjustment for afatinib and summarize the clinical characteristics of patients who continued afatinib/gefitinib beyond initial radiological progression in LUX-Lung 7. METHODS: Patients received afatinib 40 mg/day or gefitinib 250 mg/day until investigator-assessed progression or beyond if beneficial. In case of selected treatment-related adverse events (TRAEs), the afatinib dose could be reduced by 10-mg decrements to minimum 20 mg (only dose interruptions were permitted with gefitinib). RESULTS: All randomized patients were treated (afatinib, n = 160; gefitinib, n = 159). Sixty-three patients had afatinib dose reduction (< 40 mg/day; 47 within first 6 months). Dose reduction decreased TRAE incidence/severity (before vs after; all grade/grade 3: 100.0%/63.5% vs 90.5%/23.8%). There was no evidence of significant difference in PFS for patients who received < 40 mg/day vs ≥ 40 mg/day for the first 6 months [median: 12.8 vs 11.0 months; hazard ratio 1.34 (95% confidence interval 0.90-2.00)]. Twenty-four and 26 patients continued afatinib and gefitinib, respectively, beyond progression in target lesions; median time from nadir of target lesion diameters to initial progression was 6.7 months and 5.6 months. Of these patients, ~ 70% had objective response or non-complete response/non-progressive disease in non-target lesions at initial progression. CONCLUSIONS: Protocol-defined dose adjustment of afatinib may allow patients to remain on treatment longer, maximizing clinical benefit even in the presence of radiological progression.

Sequencing of therapy following first-line afatinib in patients with EGFR mutation-positive non-small cell lung cancer.

OBJECTIVES: With the availability of several epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), sequential therapy could potentially render EGFR mutation-positive non-small cell lung cancer a chronic disease in some patients. In this retrospective analysis of EGFR mutation-positive (Del19/L858R) patients receiving first-line afatinib in LUX-Lung 3, 6, and 7, we assessed uptake of, and outcomes following, subsequent therapies including the third-generation EGFR TKI, osimertinib. METHODS: Post-progression therapy data were prospectively collected during follow-up. Molecular testing of tumours at progression/discontinuation of afatinib was not mandatory. Duration of subsequent therapies, and survival following osimertinib, were calculated with Kaplan-Meier estimates. RESULTS: Among 553 patients who discontinued first-line afatinib, second-, third- and fourth-line therapy was administered in 394 (71%), 265 (48%), and 156 (28%) patients. The most common post-progression therapy was platinum-based chemotherapy (46%). Thirty-seven patients received subsequent osimertinib, 10 as second-line treatment. Median progression-free survival on afatinib in these 37 patients was 21.9 months. Median duration of osimertinib therapy was 20.2 months; median overall survival was not reached after a median follow-up of 4.7 years. CONCLUSIONS: Most patients treated with first-line afatinib received subsequent therapy. Although limited by sample size, enrichment, and a retrospective nature, data from patients who received sequential afatinib and osimertinib are encouraging, warranting further investigation.