The value measurement of emerging therapeutics in renal cell carcinoma: ASCO value framework and ESMO-MCBS.

PURPOSE: Rapid development of novel therapeutics in renal cell carcinoma (RCC) has led to financial burden for patients and society. Value including clinical benefit, toxicity affecting quality of life and cost-effectiveness are a concern, prompting the need for tools to facilitate value assessment of therapeutics. This study reviews the value assessment tools, and evaluates the value of emerging therapeutics in RCC. MATERIALS AND METHODS: Two medical oncologists used American Society of Clinical Oncology value framework (ASCO VF) v2.0 and European Society for Medical Oncology-magnitude of clinical benefit scale (ESMO-MCBS) v1.1 to phase 3 trials evaluating first-line therapy in patients with metastatic RCC. Follow-up (FU) reports and extended survival data were included. Equivocal aspects and limitations of the tools were discussed. RESULTS: Six trials (COMPARZ, CheckMate 214, JAVELIN renal 101, Keynote 426, CLEAR, and CheckMate 9ER) were assessed. The control arm was standard-of-care sunitinib in all trials. ASCO VF's net health benefit, calculated as clinical benefit, toxicity and other bonus point was 11 in pazopanib, 41.9 in nivolumab plus ipilimumab, 22.4 in axitinib plus avelumab, 48.7 in axitinib plus pembrolizumab, 35.2 in lenvatinib plus pembrolizumab, and 50.8 in cabozantinib plus nivolumab. A higher score means a greater treatment benefit. ESMO-MCBS gave grade 5 to nivolumab plus ipilimumab, 4 to pazopanib, lenvatinib plus pembrolizumab and cabozantinib plus nivolumab, 3 to axitinib plus avelumab or pembrolizumab. Both tools had unclear aspects to be applied to clinical practice, and should be more clearly defined, such as endpoint for determining survival benefits or how to standardize quality of life and toxicity. CONCLUSIONS: ASCO VF and ESMO-MCBS were applied to evaluate the newly emerging drugs in RCC and assessed their value. In-depth discussion by experts in various fields is required for appropriate clinical application in a real-world setting.

Olmutinib in T790M-positive non-small cell lung cancer after failure of first-line epidermal growth factor receptor-tyrosine kinase inhibitor therapy: A global, phase 2 study.

BACKGROUND: In this open-label, international phase 2 study, the authors assessed the efficacy and safety of olmutinib in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had a confirmed T790M mutation and disease progression on previous epidermal growth factor receptor-tyrosine kinase inhibitor therapy. METHODS: Patients aged ≥20 years received once-daily oral olmutinib 800 mg continuously in 21-day cycles. The primary endpoint was the objective response rate (patients who had a confirmed best overall response of a complete or partial response), assessed by central review. Secondary endpoints included the disease control rate, the duration of objective response, progression-free survival, and overall survival. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). RESULTS: Overall, 162 patients (median age, 63 years; women, >60%) were enrolled from 68 sites in 9 countries. At the time of database cutoff, 23.5% of enrolled patients remained on treatment. The median treatment duration was 6.5 months (range, 0.03-21.68 months). Overall, 46.3% of patients (95% CI, 38.4%-54.3%) had a confirmed objective response (all partial responses). The best overall response (the objective response rate regardless of confirmation) was 51.9% (84 patients; 95% CI, 43.9%-59.8%). The confirmed disease control rate for all patients was 86.4% (95% CI, 80.2%-91.3%). The median duration of objective response was 12.7 months (95% CI, 8.3-15.4 months). Estimated median progression-free survival was 9.4 months (95% CI, 6.9-12.3 months), and estimated median overall survival was 19.7 months (95% CI, 15.1 months to not reached). All patients experienced treatment-emergent adverse events, and 71.6% of patients had grade ≥3 treatment-emergent adverse events. CONCLUSIONS: Olmutinib has meaningful clinical activity and a manageable safety profile in patients with T790M-positive non-small cell lung cancer who received previous epidermal growth factor receptor-tyrosine kinase inhibitor therapy.

A randomised phase 2b study comparing the efficacy and safety of belotecan vs. topotecan as monotherapy for sensitive-relapsed small-cell lung cancer.

BACKGROUND: This study compared the efficacy/safety of the camptothecin analogues belotecan and topotecan for sensitive-relapsed small-cell lung cancer (SCLC). METHODS: One-hundred-and-sixty-four patients were randomised (1:1) to receive five consecutive daily intravenous infusions of topotecan (1.5 mg/m2) or belotecan (0.5 mg/m2), every 3 weeks, for six cycles. Main outcomes were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), tolerability and toxicity. The study statistical plan was non-inferiority design with ORR as the endpoint. RESULTS: In the belotecan vs. topotecan groups, ORR (primary endpoint) was 33% vs. 21% (p = 0.09) and DCR was 85% vs. 70% (p = 0.030). PFS was not different between groups. Median OS was significantly longer with belotecan than with topotecan (13.2 vs. 8.2 months, HR = 0.69, 95% CI: 0.48-0.99), particularly in patients aged <65 years, with more advanced disease (i.e., extensive-stage disease, time to relapse: 3-6 months), or Eastern Cooperative Oncology Group performance status 1 or 2. More belotecan recipients completed all treatment cycles (53% vs. 35%; p = 0.022). CONCLUSIONS: The efficacy/safety of belotecan warrants further evaluation in Phase 3 trials. Belotecan potentially offers an alternative to topotecan for sensitive-relapsed SCLC, particularly in patients aged <65 years, with more advanced disease, or poor performance.

An open-label expanded access program of afatinib in EGFR tyrosine kinase inhibitor-naïve patients with locally advanced or metastatic non-small cell lung cancer harboring EGFR mutations.

BACKGROUND: Afatinib is approved globally for EGFR-TKI treatment-naïve patients with EGFR mutation-positive non-small cell lung cancer (NSCLC). In this Korean expanded access program, we evaluated its 'real-world' safety and efficacy. METHODS: EGFR-TKI treatment-naïve patients with EGFR mutation-positive NSCLC received afatinib 40 mg/day until disease progression or other withdrawal criteria. Dose reductions were permitted for adverse events (AEs). The primary endpoint was the number of patients with AEs (CTCAE version 3.0). Other endpoints included progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and changes in investigator-assessed cancer-related symptoms. RESULTS: Eighty-eight patients received afatinib, including 27 (31%) with brain metastases and 16 (18%) with uncommon EGFR mutations. Median PFS was 17.0 months (95% confidence interval [CI] 12.9-23.3 months). Grade 3 treatment-related AEs (TRAEs) were reported in 51 (58%) patients; the most common were diarrhea (22%) and rash/acne (20%). No grade > 3 TRAEs were reported. AEs leading to dose reduction occurred in 49 (56%) patients. Treatment discontinuation due to TRAEs occurred in 4 (5%) patients. ORR was 81% overall, 89% in patients with brain metastases, and 55% in patients with uncommon mutations (excluding T790M/exon 20 insertions). Median DOR was 15.1 months (95% CI 12.4-21.4 months). Cancer-related symptoms were improved/unchanged/worsened in 34-66%/36-66%/0-3% of patients over the first year. CONCLUSIONS: No unexpected safety signals for afatinib were observed. AEs were manageable; the treatment discontinuation rate was low. Afatinib showed encouraging efficacy in a broad patient population including those with brain metastases or tumors harboring uncommon EGFR mutations. TRIALS REGISTRATION: ClinicalTrials.gov NCT01931306 ; 29/08/2013.

The implications of clinical risk factors, CAR index, and compositional changes of immune cells on hyperprogressive disease in non-small cell lung cancer patients receiving immunotherapy.

BACKGROUND: Immune checkpoint blockades (ICBs) are characterized by a durable clinical response and better tolerability in patients with a variety of advanced solid tumors. However, we not infrequently encounter patients with hyperprogressive disease (HPD) exhibiting paradoxically accelerated tumor growth with poor clinical outcomes. This study aimed to investigate implications of clinical factors and immune cell composition on different tumor responses to immunotherapy in patients with non-small cell lung cancer (NSCLC). METHODS: This study evaluated 231 NSCLC patients receiving ICBs between January 2014 and May 2018. HPD was defined as a > 2-fold tumor growth kinetics ratio during ICB therapy and time-to-treatment failure of ≤2 months. We analyzed clinical data, imaging studies, periodic serologic indexes, and immune cell compositions in tumors and stromata using multiplex immunohistochemistry. RESULTS: Of 231 NSCLC patients, PR/CR and SD were observed in 50 (21.6%) and 79 (34.2%) patients, respectively and 26 (11.3%) patients met the criteria for HPD. Median overall survival in poor response groups (HPD and non-HPD PD) was extremely shorter than disease-controlled group (SD and PR/CR) (5.5 and 6.1 months vs. 16.2 and 18.3 months, respectively, P = 0.000). In multivariate analysis, HPD were significantly associated with heavy smoker (p = 0.0072), PD-L1 expression ≤1% (p = 0.0355), and number of metastatic site ≥3 (p = 0.0297). Among the serologic indexes including NLR, PLR, CAR, and LDH, only CAR had constantly significant correlations with HPD at the beginning of prior treatment and immunotherapy, and at the 1st tumor assessment. The number of CD4+ effector T cells and CD8+ cytotoxic T cells, and CD8+/PD-1+ tumor-infiltrating lymphocytes (TIL) tended to be smaller, especially in stromata of HPD group. More M2-type macrophages expressing CD14, CD68 and CD163 in the stromal area and markedly fewer CD56+ NK cells in the intratumoral area were observed in HPD group. CONCLUSIONS: Our study suggests that not only clinical factors including heavy smoker, very low PD-L1 expression, multiple metastasis, and CAR index, but also fewer CD8+/PD-1+ TIL and more M2 macrophages in the tumor microenvironment are significantly associated with the occurrence of HPD in the patients with advanced/metastatic NSCLC receiving immunotherapy.

Should We Consider Value Frameworks for Cancer Drugs as Oncology's Landscape Evolves?; from an Oncologist Perspective in Korea.

BACKGROUND: As the role of immunotherapies and personalized medicine grow, cancer patients have faced many choices in treatments and have suffered financial toxicity. These challenges brought the need for the value framework (VF) to guide treatment decision making. METHODS: A survey was taken to 102 oncologists about perception for VF. They were asked about priorities among several considerations when they prescribe cancer drugs. Their views on the need for development and potential implications of VF in Korea were assessed, also. RESULTS: The survey shows that 90% of the respondents choose clinical efficacy as the most important value in cancer drugs selection, and the cost of drug was more weighted value in immune checkpoint inhibitors (13.7%). Approximately half (53.9%) answered that they were aware of the existing VFs. Over 90% of respondents agreed with the need for development of a VF for cancer drugs based on Korean healthcare system and further usefulness for decisions about reimbursement issues. Seventy-one percent answered that two representative VFs (American Society Clinical Oncology-VF and European Society for Medical Oncology-Magnitude of Clinical Benefit Scale) should be reflected in value measurement of cancer drugs in Korea. CONCLUSION: The Korean oncologists recognized the necessity for the clinical application of VF. Further discussion between the stakeholders should be followed to alleviate the financial burden through the value-based decision making of cancer drugs.

Anti-tumor efficacy of CKD-516 in combination with radiation in xenograft mouse model of lung squamous cell carcinoma.

BACKGROUND: Hypoxic tumors are known to be highly resistant to radiotherapy and cause poor prognosis in non-small cell lung cancer (NSCLC) patients. CKD-516, a novel vascular disrupting agent (VDA), mainly affects blood vessels in the central area of the tumor and blocks tubulin polymerization, thereby destroying the aberrant tumor vasculature with a rapid decrease in blood, resulting in rapid tumor cell death. Therefore, we evaluated the anti-tumor efficacy of CKD-516 in combination with irradiation (IR) and examined tumor necrosis, delayed tumor growth, and expression of proteins involved in hypoxia and angiogenesis in this study. METHODS: A xenograft mouse model of lung squamous cell carcinoma was established, and the tumor was exposed to IR 5 days per week. CKD-516 was administered with two treatment schedules (day 1 or days 1 and 5) 1 h after IR. After treatment, tumor tissues were stained with hematoxylin and eosin, and pimonidazole. HIF-1α, Glut-1, VEGF, CD31, and Ki-67 expression levels were evaluated using immunohistochemical staining. RESULTS: Short-term treatment with IR alone and CKD-516 + IR (d1) significantly reduced tumor volume (p = 0.006 and p = 0.048, respectively). Treatment with CKD-516 + IR (d1 and d1, 5) resulted in a marked reduction in the number of blood vessels (p < 0.005). More specifically, CKD-516 + IR (d1) caused the most extensive tumor necrosis, which resulted in a significantly large hypoxic area (p = 0.02) and decreased HIF-1α, Glut-1, VEGF, and Ki-67 expression. Long-term administration of CKD-516 + IR reduced tumor volume and delayed tumor growth. This combination also greatly reduced the number of blood vessels (p = 0.0006) and significantly enhanced tumor necrosis (p = 0.004). CKD-516 + IR significantly increased HIF-1α expression (p = 0.0047), but significantly reduced VEGF expression (p = 0.0046). CONCLUSIONS: Taken together, our data show that when used in combination, CKD-516 and IR can significantly enhance anti-tumor efficacy compared to monotherapy in lung cancer xenograft mice.

Impact of Epidermal Growth Factor Receptor Mutation on Clinical Outcomes of Nintedanib Plus Docetaxel in Patients with Previously Treated Non-Small Cell Lung Cancer from the Korean Named Patient Program.

OBJECTIVES: Anti-angiogenic agents are reported to exert clinical activity on epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancers. We evaluated the clinical outcomes of nintedanib and docetaxel in refractory NSCLC according to EGFR mutation status during the Korean nintedanib named patient program. METHODS: Docetaxel was administered either 75 or 37.5 mg/m2 on D1, D8 q every 3 weeks for 4-6 cycles plus nintedanib 200 mg orally twice daily until disease progression or unacceptable toxicity. RESULTS: Sixty-two patients were enrolled for study. Twenty-eight patients with activating EGFR mutations progressed after EGFR-tyrosine kinase inhibitors (TKI) therapy and 25 out of 28 patients showing progression after platinum doublet chemotherapy were enrolled. The objective response rate was 29% and median PFS and OS were 3.9 months and 11.7 months. Based on the EGFR mutation status, the objective response rate was 39.3 vs. 21.9% (EGFR mut(+) vs. EGFR mut(-), p = 0.142) and median PFS was 6.5 vs. 3.3 months (EGFR mut(+) vs. EGFR mut(-), p = 0.009). No treatment-related deaths were reported. The most frequent drug-related adverse events (AE) were neutropenia (53.2%) and diarrhea (37.1%). Treatment in 12 patients (19.3%) was permanently discontinued due to AEs without disease progression. CONCLUSIONS: Our data indicated that nintedanib-docetaxel combination could be considered to be effective treatment in EGFR TKI-resistant EGFR mutant NSCLC.

The effect of antibiotics on the clinical outcomes of patients with solid cancers undergoing immune checkpoint inhibitor treatment: a retrospective study.

BACKGROUND: This study aimed to assess the effect of antibiotics on the clinical outcomes of patients with solid cancers undergoing treatment with immune checkpoint inhibitors (ICIs). METHODS: The medical records of 234 patients treated with ICIs for any type of solid cancer between February 2012 and May 2018 at the Seoul St. Mary's Hospital were retrospectively reviewed. The data of patients who received antibiotics within 60 days before the initiation of ICI treatment were analyzed. The patients' responses to ICI treatment and their survival were evaluated. RESULTS: Non-small-cell lung carcinoma was the most common type of cancer. About half of the patients were treated with nivolumab (51.9%), and cephalosporin (35.2%) was the most commonly used class of antibiotics. The total objective response rate was 21%. Antibiotics use was associated with a decreased objective response (odds ratio 0.466, 95% confidence interval [CI] 0.225-0.968, p = 0.040). The antibiotics group exhibited shorter progression-free survival (PFS) and overall survival (OS) than the no antibiotics group (median PFS: 2 months vs. 4 months, p < 0.001; median OS: 5 months vs. 17 months, p < 0.001). In the multivariate analysis, antibiotics use was a significant predictor of patient survival (PFS: hazard ratio [HR] 1.715, 95% CI 1.264-2.326, p = 0.001; OS: HR 1.785, 95% CI 1.265-2.519, p = 0.001). CONCLUSIONS: The use of antibiotics may affect the clinical outcomes of patients with solid cancers treated with ICIs. Careful prescription of antibiotics is warranted in candidates who are scheduled for ICI treatment. TRIAL REGISTRATION: Not applicable (retrospective study).

Clinical activity of ASP8273 in Asian patients with non-small-cell lung cancer with EGFR activating and T790M mutations.

Epidermal growth factor receptor (EGFR)-activating mutations confer sensitivity to tyrosine kinase inhibitor (TKI) treatment for non-small-cell lung cancer (NSCLC). ASP8273 is a highly specific, irreversible, once-daily, oral, EGFR TKI that inhibits both activating and resistance mutations. This ASP8273 dose-escalation/dose-expansion study (NCT02192697) was undertaken in two phases. In phase I, Japanese patients (aged ≥20 years) with NSCLC previously treated with ≥1 EGFR TKI received escalating ASP8273 doses (25-600 mg) to assess safety/tolerability and to determine the maximum tolerated dose (MTD) and/or the recommended phase II dose (RP2D) by the Bayesian Continual Reassessment Method. In phase II, adult patients with T790M-positive NSCLC in Japan, Korea, and Taiwan received ASP8273 at RP2D to further assess safety/tolerability and determine antitumor activity, which was evaluated according to Simon's two-stage design (threshold response = 30%, expected response = 50%, α = 0.05, ß = 0.1). Overall, 121 (n = 45 [33W/12M] phase I, n = 76 [48W/28M]) phase 2) patients received ≥1 dose of ASP8273. In phase I, RP2D and MTD were established as 300 and 400 mg, respectively. As 27 of the 63 patients treated with ASP8273 300 mg achieved a clinical response, ASP8273 was determined to have antitumor activity. The overall response rate at week 24 in all patients was 42% (n = 32/76; 95% confidence interval, 30.9-54.0). Median duration of progression-free survival was 8.1 months (95% confidence interval, 5.6, upper bound not reached). The most commonly reported treatment-related adverse event in phase II was diarrhea (57%, n = 43/76). ASP8273 300 mg was generally well tolerated and showed antitumor activity in Asian patients with both EGFR-activating and T790M mutations.

Phase I Pharmacokinetic Study of Nivolumab in Korean Patients with Advanced Solid Tumors.

LESSONS LEARNED: This pharmacokinetic study of nivolumab showed that there is little ethnic difference in the handling of nivolumab.Nivolumab was well tolerated in Korean patients. BACKGROUND: This phase I study of nivolumab, an anti-programmed cell death-1 (anti-PD-1) monoclonal antibody, investigated the pharmacokinetics and safety of nivolumab in Korean patients with advanced solid tumors. Findings were compared with results from Japan and the U.S. MATERIALS AND METHODS: In this two-part study, patients received a single dose of nivolumab (1, 3, and 10 mg/kg; ONO-4538-13) and were followed up for 3 weeks. Those who met the required criteria proceeded to the second part (ONO-4538-14), and received the same dose as in part one every 2 weeks. RESULTS: Six patients per dose level were enrolled (n = 18). The mean elimination half-life of nivolumab among the groups ranged from 15.0 to 19.1 days. The maximum serum concentration and area under serum concentration-time curve increased almost dose-proportionally at doses from 1 to 10 mg/kg. Adverse drug reactions (ADRs; mostly grade ≤2) were reported in seven patients (38.9%). ADRs grade ≥3 occurred in one patient (5.6%; pneumonitis). Three patients (16.7%) developed ADRs related to thyroid dysfunction. CONCLUSION: The pharmacokinetic parameters of nivolumab were similar among patients from Korea, Japan, and the U.S. The safety profile was consistent with findings from previous studies.

Patient and oncologist perceptions regarding symptoms and impact on quality-of-life of oral mucositis in cancer treatment: results from the Awareness Drives Oral Mucositis PercepTion (ADOPT) study.

PURPOSE: This descriptive cross-sectional survey aims to assess the level of concordance between the perspectives of oncologists and those of patients regarding oral mucositis (OM) symptoms, and the impact of OM on various aspects of daily living and concurrent cancer management. METHODS: Oncologists involved in OM management (n = 105), and patients who developed OM during cancer treatment (n = 175), were recruited from seven Asian countries. Oncologists completed a face-to-face, quantitative interview; patients completed a face-to-face interview, and a self-reported questionnaire. RESULTS: Oncologists and patients ranked treatment-induced OM among the three most important toxicities of cancer therapy requiring intervention. The most frequent OM symptoms reported by patients were oral ulcers (74%), dry mouth (73%), and difficulty swallowing (62%). Oncologists expected mild OM symptoms to last slightly longer than 1 week, whereas patients reported mild symptoms for more than 2 weeks. In mild-to-moderate OM, oncologists underestimated patients' pain experience. Overall, only 45% of oncologists said they would initiate OM prophylaxis when cancer therapy started. Of the 87% of patients who said they used their prescribed medications, only 16% reported using prophylactically prescribed medication. While oncologists' concerns related to the delays and interruptions of cancer treatment, patients tended to focus on the effects of OM on eating, drinking, and talking. CONCLUSIONS: Oncologists' and patients' perceptions about treatment-induced OM differ. To overcome discordant perspectives, there is a need to raise general awareness and improve proactive management of OM. As noted in recent guidelines, supportive cancer care is critical for ensuring optimal therapy and for improving the patient's experience.

Clinical Significance of C-MET Overexpression and Epidermal Growth Factor Receptor Mutation in Platinum-Based Adjuvant Chemotherapy Outcome in Surgically Resected Lung Adenocarcinoma.

PURPOSE: We retrospectively assessed the role of C-MET expression and epidermal growth factor receptor (EGFR) mutation on survival following platinum-based adjuvant chemotherapy. The impact of C-MET on survival was also investigated in relation to EGFR mutation status. METHODS: We enrolled 311 patients with resected lung adenocarcinoma (high-risk stage 1B-3A), and performed immunohistochemistry (IHC) using C-MET- and mutant EGFR (EGFRmut)-specific antibodies in tissue microarrays. RESULTS: Adjuvant chemotherapy was administered to 151 patients, 96 of whom relapsed and 85 died by the end of the study. On IHC, C-MET and EGFRmut were positive in 141 (45.3 %) and 88 (28.3 %) cases, respectively. On univariate analysis, adjuvant chemotherapy prolonged relapse-free survival (RFS) and overall survival (OS) in C-MET(+) patients (RFS p = 0.035; OS p = 0.013) but not in C-MET(-) patients. On multivariate analysis, adjuvant chemotherapy was a positive independent prognostic factor in C-MET(+) (RFS p = 0.013; OS p = 0.006) but not in C-MET(-) patients. In addition, univariate analysis showed no effect of EGFRmut status on RFS and OS after chemotherapy, whereas multivariate analysis revealed that adjuvant chemotherapy increased RFS in both EGFRmut(+) and EGFRmut(-) patients [EGFRmut(+) p = 0.033; EGFRmut(-) p = 0.030]. C-MET was a negative prognostic factor for RFS (p = 0.045) and OS (p = 0.007) in the EGFRmut(-) group but not in the EGFRmut(+) group, on multivariate analysis. CONCLUSIONS: Our data indicate that patients with C-MET overexpression should be considered for adjuvant chemotherapy, and that C-MET negatively correlates with survival in patients with wild-type, but not mutant, EGFR.

18F-FDG PET/CT and histology for diagnosing recurrent/remnant tumors in head and neck cancer patients treated with radiotherapy.

OBJECTIVE: The aim of this study was to assess the diagnostic performance of fluorine-18-fluoro-2-deoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) for locoregional recurrent/residual tumor in patients with head and neck cancer (HNC) who underwent previous radiotherapy (RT). SUBJECTS AND METHODS: 18F-FDG PET/CT images from patients with HNC who previously underwent RT were retrospectively reviewed. Only cases with histological confirmation within 4 weeks of PET/CT imaging were included. Standardized uptake values were obtained for lesions and PET/CT findings were compared with histological results. RESULTS: Of 181 cases, 114 (63%) were histologically confirmed as malignant and 67 (37%) as benign. The sensitivity, specificity, and accuracy of PET/CT were 93%, 64%, and 82%, respectively. Inflammation was the most common cause of false positives and small tumor volume and low 18F-FDG avidity were the causes of false negatives. PET/CT had 100% sensitivity and 56% specificity for detecting recurrent or residual disease within 12 weeks after RT and 93% sensitivity and 64% specificity, more than 12 weeks after RT. The frequency of false positives in PET/CT images within 12 weeks of RT was similar to the results obtained 12 weeks after RT (15% vs. 14%). False positives were more frequent in PET/CT cases after two-dimensional or three-dimensional conformal RT than in those after intensity-modulated RT, although not statistically significant (15% vs. 9%, p>0.05). CONCLUSION: 18F-FDG PET/CT might aid the diagnosis of locoregional residual/recurrent tumors in patients with HNC previously treated with RT. Inflammation was the main cause of false positives regardless of the interval between RT and PET/CT, even several years after RT. Therefore, histological verification of positive PET/CT findings should be conducted during follow-up of HNC patients treated with RT.

Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study.

BACKGROUND: Osimertinib (AZD9291) is an oral, potent, irreversible EGFR tyrosine-kinase inhibitor selective for EGFR tyrosine-kinase inhibitor sensitising mutations, and the EGFR Thr790Met resistance mutation. We assessed the efficacy and safety of osimertinib in patients with EGFR Thr790Met-positive non-small-cell lung cancer (NSCLC), who had progressed after previous therapy with an approved EGFR tyrosine-kinase inhibitor. METHODS: In this phase 2, open-label, single-arm study (AURA2), patients aged at least 18 years with centrally confirmed EGFR Thr790Met-positive mutations, locally advanced or metastatic (stage IIIB/IV) NSCLC who progressed on previous EGFR tyrosine-kinase inhibitor therapy received osimertinib 80 mg orally once daily; treatment could continue beyond progression if the investigator observed a clinical benefit. Patients with asymptomatic, stable CNS metastases not requiring steroids were allowed to enrol. The primary endpoint was the proportion of patients achieving an objective response by blinded independent central review using Response Evaluation Criteria in Solid Tumors, version 1.1. Response endpoints were assessed in the evaluable for response analysis set (ie, all patients who received at least one dose of osimertinib and had measurable disease at baseline according to blinded independent central review). Other endpoints and safety were assessed in all patients receiving at least one osimertinib dose (full analysis set). The study is ongoing and patients are still receiving treatment. This study is registered with ClinicalTrials.gov, number NCT02094261. FINDINGS: Between May 20, 2014, and Sept 12, 2014, 472 patients were screened, of whom 210 started osimertinib treatment between June 13, 2014, and Oct 27, 2014; 11 patients were excluded from the evaluable for response analysis set (n=199) due to absence of measurable disease at baseline by blinded independent central review. At data cutoff (Nov 1, 2015), 122 (58%) patients remained on treatment. The median duration of follow-up was 13·0 months (IQR 7·6-14·2). 140 (70%; 95% CI 64-77) of 199 patients achieved an objective response by blinded independent central review: confirmed complete responses were achieved in six (3%) patients and partial responses were achieved in 134 (67%) patients. The most common all-causality grade 3 and 4 adverse events were pulmonary embolism (seven [3%]), prolonged electrocardiogram QT (five [2%]), decreased neutrophil count (four [2%]), anaemia, dyspnoea, hyponatraemia, increased alanine aminotransferase, and thrombocytopenia (three [1%] each). Serious adverse events were reported in 52 (25%) patients, of which 11 (5%) were investigator assessed as possibly treatment-related to osimertinib. Seven deaths were due to adverse events; these were pneumonia (n=2), pneumonia aspiration (n=1), rectal haemorrhage (n=1), dyspnoea (n=1), failure to thrive (n=1), and interstitial lung disease (n=1). The only fatal event assessed as possibly treatment-related by the investigator was due to interstitial lung disease. INTERPRETATION: Osimertinib showed clinical activity with manageable side-effects in patients with EGFR Thr790Met-positive NSCLC. Therefore, osimertinib could be a suitable treatment for patients with EGFR Thr790Met-positive disease who have progressed on an EGFR tyrosine-kinase inhibitor. FUNDING: AstraZeneca.

Phase II evaluation of LY2603618, a first-generation CHK1 inhibitor, in combination with pemetrexed in patients with advanced or metastatic non-small cell lung cancer.

Introduction LY2603618 is a selective inhibitor of checkpoint kinase 1 (CHK1) protein kinase, a key regulator of the DNA damage checkpoint, and is predicted to enhance the effects of antimetabolites, such as pemetrexed. This phase II trial assessed the overall response rate, safety, and pharmacokinetics (PK) of LY2603618 and pemetrexed in patients with non-small cell lung cancer (NSCLC). Methods In this open-label, single-arm trial, patients with advanced or metastatic NSCLC progressing after a prior first-line treatment regimen (not containing pemetrexed) and Eastern Cooperative Oncology Group performance status ≤2 received pemetrexed (500 mg/m(2), day 1) and LY2603618 (150 mg/m(2), day 2) every 21 days until disease progression. Safety was assessed using Common Terminology Criteria for Adverse Events v3.0. Serial blood samples were collected for PK analysis after LY2603618 and pemetrexed administration. Expression of p53, as measured by immunohistochemistry and genetic variant analysis, was assessed as a predictive biomarker of response. Results Fifty-five patients were enrolled in the study. No patients experienced a complete response; a partial response was observed in 5 patients (9.1 %; 90 % CI, 3.7-18.2) and stable disease in 20 patients (36.4 %). The median progression-free survival was 2.3 months (range, 0-27.1). Safety and PK of LY2603618 in combination with pemetrexed were favorable. No association between p53 status and response was observed. Conclusions There was no significant clinical activity of LY2603618 and pemetrexed combination therapy in patients with advanced NSCLC. The results were comparable with historical pemetrexed single-agent data, with similar safety and PK profiles being observed.

Serum lactate dehydrogenase levels at presentation in stage IV non-small cell lung cancer: predictive value of metastases and relation to survival outcomes.

This study aimed to evaluate the clinical correlations between serum lactate dehydrogenase (LDH) levels and tumor characteristics and to investigate the prognostic impact of serum LDH levels in advanced non-small cell lung cancer (NSCLC). A total of 394 patients were included in the present study between June 2007 and January 2013. All eligible patients had serum LDH levels available before treatment, and whole-body metastatic extent was measured using whole-body metastatic scores, as determined by 18(F)-fludeoxyglucose positron emission tomography scans from 1 to 7 as the sum of each metastatic region. The diagnostic cutoff value for an abnormal serum LDH level was 450 IU/L. The median serum LDH level was 477 IU/L (range, 113-2850), and 224 (56.9 %) patients had abnormal serum LDH levels. The serum LDH levels showed no significant associations with age, gender, histology, tumor differentiation, and smoking history. However, the proportion of patients with abnormal serum LDH levels was statistically significantly higher in the high total metastatic score group (scores 3-7) than in the low total metastatic score group (scores 1-2) (65.3 vs 50.4 %, p = 0.001). In a multivariate survival analysis, age (p = 0.001), gender (p = 0.001), histology (p = 0.003), tumor differentiation (p = 0.001), Eastern Cooperative Oncology Group (ECOG) performance status (p = 0.001), LDH levels (p = 0.046), and treatment factors (p = 0.001) proved to be independent prognostic factors for survival outcomes. The results of this study suggest that the serum LDH levels at presentation may be significantly correlated with whole-body tumor extent and might independently but modestly prognosticate OS in stage IV NSCLC.

Total Lesion Glycolysis Using ¹8F-FDG PET/CT as a Prognostic Factor for Locally Advanced Esophageal Cancer.

Standardized uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) have been considered prognostic factors for survival in many cancers. However, their prognostic value for radiotherapy-treated squamous esophageal cancer has not been evaluated. In this study, SUV, MTV, and TLG were measured to predict their prognostic role in overall survival (OS) in 38 esophageal cancer patients who had undergone (18)F-FDG PET/CT before radiotherapy. TLG demonstrated higher sensitivity and specificity for predicting OS than MTV and SUV; and a better OS was observed in patients with low TLG compared to those with high TLG in locally advanced disease (OS, 46.9 months; 95% confidence interval [CI], 33.50-60.26 vs. 25.3 months; 95% CI, 8.37-42.28; P=0.003). Multivariate analyses in these patients determined that TLG and the use of combination chemotherapy were the independent prognostic factors for OS (hazard ratio [HR], 7.12; 95% CI, 2.038-24.857; P=0.002 and HR, 6.76; 95% CI, 2.149-21.248; P=0.001, respectively). These results suggest that TLG is an independent prognostic factor for OS and a better predictor of survival than MTV and SUV in patients with locally advanced esophageal cancer treated with radiotherapy.

A Randomized, Multicenter, Phase II Study of Cetuximab With Docetaxel and Cisplatin as Induction Chemotherapy in Unresectable, Locally Advanced Head and Neck Cancer.

BACKGROUND: We investigated the efficacy of cetuximab when added to induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) in patients with locally advanced head and neck squamous cell carcinoma. METHODS: Patients were randomized to receive three cycles of docetaxel and cisplatin (TP regimen) with or without cetuximab (TP plus cetuximab [CTP] vs. TP) as induction chemotherapy. Patients in the CTP arm received CCRT with cetuximab and cisplatin, whereas patients in the TP arm received cisplatin alone. The primary endpoint was the objective response rate (ORR) after induction chemotherapy. RESULTS: Overall, 92 patients were enrolled. The ORRs for induction chemotherapy in the CTP and TP arms were not different (81% vs. 82%). Adding cetuximab lowered the completion rate of induction chemotherapy and CCRT and resulted in more frequent dose reductions of the induction chemotherapy, although this did not reach statistical significance. In the CTP and TP arms, respectively, the 3-year progression-free survival (PFS) rates were 70% and 56% (p = .359), and the overall survival (OS) rates were 88% and 74% (p = .313). When limited to patients who completed induction chemotherapy, 3-year PFS rates of 78% and 59% (p = .085) and OS rates of 94% and 73% (p = .045) were observed in the CTP and TP arms, respectively. CONCLUSION: Adding cetuximab to sequential treatment did not increase the treatment efficacy and resulted in greater toxicity. In the intent-to-treat population, neither PFS nor OS was improved by the addition of cetuximab to sequential treatment; however, a suggestion of improved survival outcomes was observed in patients completing cetuximab-containing induction chemotherapy.

Ramosetron Versus Ondansetron in Combination With Aprepitant and Dexamethasone for the Prevention of Highly Emetogenic Chemotherapy-Induced Nausea and Vomiting: A Multicenter, Randomized Phase III Trial, KCSG PC10-21.

BACKGROUND: A combination of serotonin receptor (5-hydroxytryptamine receptor type 3) antagonists, NK-1 receptor antagonist, and steroid improves the complete response (CR) of chemotherapy-induced nausea and vomiting (CINV) in cancer patients. Ramosetron's efficacy in this triple combination regimen has not been investigated. This prospective, multicenter, single-blind, randomized, phase III study compares a combination of ramosetron, aprepitant, and dexamethasone (RAD) with a combination of ondansetron, aprepitant, and dexamethasone (OAD) to prove the noninferiority of RAD in controlling highly emetogenic CINV. METHODS: Aprepitant and dexamethasone were orally administered for both arms. Ramosetron and ondansetron were intravenously given to the RAD and OAD groups. The primary endpoint was no vomiting and retching and no need for rescue medication during the acute period (day 1); the noninferiority margin was -15%. RESULTS: A total of 299 modified intention-to-treat cancer patients who received RAD (144 patients) and OAD (155 patients) were eligible for the efficacy analysis. The CR rates of RAD versus OAD were 97.2% versus 93.6% during the acute period, 77.8% versus 73.6% during the delayed period (day 2-5), and 77.1% versus 71.6% during the overall period. Furthermore, RAD was noninferior to OAD in subgroups stratified by age, cancer type, chemotherapeutic agents, and schedule. Repeated measures analysis showed that in male patients, RAD was superior to OAD. Profiles of adverse events were similar in both groups. CONCLUSION: RAD is as effective and tolerable as OAD for CINV prevention in patients receiving highly emetogenic chemotherapy. Ramosetron could be considered one of the best partners for aprepitant.