Background

TNM stage is still the only prognostic tool used in clinical practice to treat patients but it fails to accurately predict outcomes. Categorization of locally advanced rectal cancers into distinct subtypes using a combination of qPCR-based biomarkers could provide insight into variability in outcomes.

Methods

We used a PCR-based assay to detect 30 genes (LARCassigner-30) in 197 locally advanced rectal cancer samples, collected prospectively from patients treated with neoadjuvant chemoradiation and surgery from January 2007 to December 2012 in Fudan University Shanghai Cancer Center. 197 patients were randomly divided into training queuing of 98 cases and validation of the cohort of 99 cases. Median follow-up time is 58 months. Association with 5-year overall survival, disease-free survival, recurrent rate and metastatic rate was evaluated using Cox proportional hazards models.

Results

Baseline clinical characteristics and postoperative pathological features were similar between the training cohort and the validation cohort. The overall survival rate of LARCassigner-30 type 1 patients was lower than that of type 2 patients in the training and validation cohorts (p < 0.01), tumor-free survival rate decreased (p < 0.01); local recurrence rate increased (p < 0.01), distant metastasis rate increased (p < 0.01), the difference was statistically significant. In the training cohort, LARCassigner-30 type 1 patients with locally advanced rectal cancer were found to have poorer response to neoadjuvant chemoradiation than type 2 patients (p = 0.023), but they were not verified in the validation cohort.

Conclusions

We developed qPCR-based classifiers LARCassigner-30 that performs well at predicting the outcomes in locally advanced rectal cancer.

Legal entity responsible for the study

Institutional Review Board of Fudan University Shanghai Cancer Center.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

The oral, irreversible ErbB family blocker, afatinib, is approved as first-line treatment for patients (pts) with EGFR mutation-positive (EGFRm+) NSCLC, and for second-line treatment in EGFR tyrosine kinase inhibitor (TKI)-naïve pts with EGFRm+ NSCLC progressing on or after platinum-based chemotherapy. In the LUX-Lung 2 study, second-line afatinib demonstrated clinical activity and an acceptable safety profile in pts with advanced NSCLC harbouring common EGFR mutations (Del19/L858R) following chemotherapy; however, the starting dose was 50 mg/day for most pts. Here, we report efficacy and safety of second-line afatinib at the recommended dose of 40 mg/day in this pt population.

Methods

In this open-label, single-arm Phase IV study, TKI-naïve pts with EGFRm + (Del19/L858R) NSCLC who progressed after failure of first-line chemotherapy received afatinib (starting dose 40 mg/day) until disease progression or other reasons necessitating withdrawal. The primary endpoint was investigator-assessed confirmed objective response (OR); secondary endpoints were PFS, disease control and safety.

Results

The study was conducted across 24 sites in 7 countries. 60 pts were enrolled into the study and treated with afatinib for a median duration of 11.5 months. The mean age of pts was 55.9 years; 55% were female; 15% had brain metastases. An OR was achieved by 50% of treated pts; median duration of response was 13.8 months. 50 pts (83%) achieved disease control; median duration was 11.9 months. Among pts with baseline brain metastases (BM) at entry (N = 9), 67% achieved PR, 22% had SD and 11% had PD. 39 pts experienced an event contributing to PFS, with median PFS of 10.9 months. The most common treatment-related adverse events of any grade were diarrhoea (72%), rash/acne (58%), and paronychia (27%); no deaths were related to treatment.

Conclusions

At the recommended starting dose of 40 mg/day, second-line afatinib demonstrated efficacy and a tolerable safety profile in pts with EGFRm + (Del19/L858R) NSCLC, including those with BM. The outcomes are consistent with previous studies of afatinib. These findings support the use of second-line afatinib in chemotherapy pre-treated pts.

Editorial acknowledgement

Hashem Dbouk.

Clinical trial identification

NCT02208843.

Legal entity responsible for the study

Boehringer Ingelheim.

Funding

Boehringer Ingelheim.

Disclosure

S.L. Geater: Honoraria: AstraZeneca, Boehringer Ingelheim; Research Funding Samsung, AstraZeneca, Boehringer Ingelhiem, Roche. D. Jovanovic: Advisory board: Member of BI AdB. V. Sriuranpong: Corporate-sponsored research: Boehringer Ingelheim. A. Cseh: Employment: Boehringer Ingelheim Stock; Other ownership: Meda. R. Gaafar: Membership of an advisory board: Boehringer Ingelheim, Eli Lilly, AstraZeneca, MSD; Corporate sponsored research between company and NCI, Cairo University; Investigator: Roche International, BI, MSD. All other authors have declared no conflicts of interest.

Background

Despite significant improvements in the treatment of early HCC, curative therapies remain associated with high recurrence rates (≈70% at 5 y) (EASL. J Hepatol 2018), and therefore, adjuvant therapies are needed. Nivolumab (NIVO) has demonstrated durable tumor responses and a manageable safety profile in patients (pts) with advanced HCC, regardless of HCC etiology (CheckMate-040 study) (El-Khoueiry, et al. Lancet 2017). Additionally, NIVO has shown clinical benefit as adjuvant therapy in melanoma (CheckMate-238 study) (Weber, et al. NEJM 2017). This phase 3, randomized, double-blind, placebo-controlled study will evaluate the safety and efficacy of adjuvant NIVO in pts with HCC who are at high risk of recurrence after curative hepatic resection or ablation, a population for whom no effective therapies are currently available.

Trial design

The trial will include 530 pts aged ≥18 y with a first diagnosis of HCC (any etiology) who are at high risk for HCC recurrence after curative resection or ablation, and who have well-preserved liver function (Child-Pugh score 5 or 6), randomized (1:1) to receive NIVO (480 mg intravenous Q4W) or placebo (PBO). Additional eligibility criteria include Eastern Cooperative Oncology Group performance status of 0 or 1, no evidence of tumor metastasis, no prior therapy for HCC (including loco-regional therapies), and no liver transplant. Pts will be treated until recurrence per blinded independent central review (BICR) assessment, unacceptable toxicity, or withdrawal, or for up to 1 y total duration. Survival follow-up will continue for up to 5 y. The primary endpoint is to compare recurrence-free survival, per BICR assessment. Secondary endpoints include overall survival and time to recurrence (defined as time from randomization to first documented disease recurrence). The trial will be open for enrollment in 20 countries worldwide and is currently recruiting. Previously presented at ESMO 2018, FPN 783TiP, Exposito et al. Reused with permission.

Editorial acknowledgement

Hammons PhD, and Christine Craig of Parexel, funded by Bristol-Myers Squibb.

Clinical trial identification

NCT03383458.

Legal entity responsible for the study

Bristol-Myers Squibb.

Funding

Bristol-Myers Squibb.

Disclosure

M.J. Jimenez Exposito: Employment, stock and other ownership interests: Bristol-Myers Squibb. L.A. Balart: Advisory committees: Genentech, Janssen, AbbVie; Grant, research support: Merck, Roche/Genentech, Bayer, Hyperion, AbbVie, Takeda, GI Dynamics, Gilead, BMS, Eisai, Vertex; Speaking and teaching: Merck. A. Heurgue-Berlot: Personal fees: Gilead, Abbvie, MSD, outside the submitted work. V. Poulart: Personal fees, stock owner: Bristol-Myers Squibb. M. Shimada: Grants: Bristol-Myers Squibb, outside the submitted work. J-H. Yoon: Grants: Bayer HealthCare Pharmaceuticals, outside the submitted work. All other authors have declared no conflicts of interest.

Case Summary

Background: Intubated patients due to tracheal stenosis by the tumor rarely received radiotherapy because most of radiation oncologists think radiotherapy for these patients very risky. Therefore, the effect of radiotherapy for these patients is poorly identified. The objective of this study is to investigate the effective of radiotherapy for intubated patients due to tracheal stenosis by the tumor.
Methods: A total of 3 patients with tracheal intubation due to tracheal stenosis by squamous cell carcinoma of the lung undergoing radiotherapy in 2016 were identified.
Results: Three patients were admitted to the hospital because of tracheal stenosis due to locally advanced squamous cell carcinoma of the lung. Patient age was 67, 75, and 84 years old, respectively. Just a month before admission, their Eastern Cooperative Oncology Group Performance Status was 0. After admission, bronchoscopy with transbronchial biopsy was taken and they got intubated on the mechanical ventilator. The prescribed dose was 28 Gy at 7 Gy per fraction, 20 Gy at 4 Gy per fraction, and 25 Gy at 5 Gy per fraction. Two patients were extubated on Day 14 of admission. They were also able to return to their social activities one month after admission. They were given re-irradiation 4 months after completion of radiotherapy because of the loco-regional recurrence. One survived for 21 months without any treatment after re-irradiation. The other was alive 7 months after admission, but the follow-up was interrupted after that. Unfortunately, one patient was discontinued radiotherapy at 16 Gy because of her bad general medical condition. She died due to acute respiratory distress syndrome on day 22. No one was given chemotherapy. Acute toxicity related to radiotherapy was not experienced. Malfunction of the ventilator was concerned, but no ventilator broke down during radiotherapy.
Conclusion: Palliative radiotherapy enabled two of three patients to relief symptoms and return to their social activities. Our experiences suggest that intubated patients due to tracheal stenosis by squamous cell carcinoma of the lung can receive radiotherapy safely and can be rehabilitated well.

Background

Alterations in mitochondrial DNA (mtDNA) have been identified in several types of solid tumors. However, the clinical significance of plasma mtDNA content in lung cancer remains unknown. Thus, we explore the diagnostic and prognostic value of plasma mtDNA quantification in lung cancer patients.

Methods

Plasma mtDNA copy numbers of lung cancer patients (n = 128) and healthy individuals (n = 107) were quantified with real-time quantitative PCR.

Results

Plasma mtDNA in patients and healthy controls were 0.89 × 10⁴ and 1.37 × 10⁴ copies/μl, respectively (P < 0.0001). And lower plasma mtDNA content were associated with tumor size, lymph node metastases, distant metastases and serum carcinoembryonic antigen level (P < 0.05), but were not associated with pathological type, age, gender, or main driver gene mutation status (P > 0.05). Plasma mtDNA facilitated detection of lung cancer at a threshold of 1.19 × 104 copies/μl with a sensitivity of 71.1% and specificity of 70.1%, as determined in receiver operating characteristic curve analysis. Advanced stage (III and IV) patients with a lower mtDNA copy number (cut-off: 1.02 × 104 copies/μl) tend to have poor prognosis (P < 0.05).

Conclusions

These results indicated that plasma mtDNA content would be a promising and complimentary candidate for diagnosis and prognostic prediction for lung cancer.

Editorial acknowledgement

No.

Clinical trial identification

No.

Legal entity responsible for the study

Hunan Cancer Hospital.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.

Background

Ceritinib (CERI) has demonstrated in the ASCEND-4 phase III trial to improve progression free survival (PFS) compared with chemotherapy in previously untreated lymphoma kinase-positive (ALK+) advanced non-small cell lung cancer (NSCLC). The ASCEND-8 bioequivalence trial confirmed similar pharmacokinetics and better safety profile with a lower dose of CERI at 450mg daily with food. Our objective is to assess the cost-effectiveness of CERI versus crizotinib in the treatment of ALK+ NSCLC in Hong Kong (HK).

Methods

A partitioned survival model with three health states was built to evaluate costs and effectiveness associated with first-line treatment with CERI. Efficacy inputs (PFS and OS) of CERI were estimated using data from ASCEND-4 and extrapolated beyond the trial period using parametric survival models. Relative efficacy of CERI vs. CRIZO was estimated using matching-adjusted indirect comparison based on ASCEND-4 and PROFILE 1014 data. Frequencies of adverse events were obtained from an interim analysis of the ASCEND-8 (cut-off: 26/7/17). Drug acquisition, administration and medical costs associated with each health state were obtained. The incremental cost effectiveness ratio (ICER) per quality-adjusted life years (QALYs) was the main outcome. Deterministic and probabilistic sensitivity analyses were performed to test the robustness of the results.

Results

ICER for CERI as a first line treatment for ALK+ NSCLC was USD 13,343 compared with CRIZO. The resulting ICER is significantly lower than the WHO threshold of three times gross domestic product (GDP) per capita (currently at USD 119,274) and below the local ICER threshold reported for HK (USD 24,302 – 40,202) . Results were robust to sensitivity analyses, including analysis to obtain frequencies of adverse events from ASCEND-4 trial data (ICER of USD17,051).

Conclusions

Compared with CRIZO, CERI offers a cost-effective option in the treatment of previously untreated ALK+ advanced NSCLC in HK.

Legal entity responsible for the study

The Chinese University of Hong Kong.

Funding

Novartis Oncology.

Disclosure

H.H. Loong: Advisory board: Novartis (not pertaining to this submission), Boehringer Ingelheim, Roche; Research Funding MSD, Mundipharma; Speakers bureau: Abbvie, Bayer, Eisai, Novartis (not pertaining to this submission). C.P.K. Chan, A. Chang, M. Gibbs: Employee: Novartis Oncology. All other authors have declared no conflicts of interest.

Background

The highly potent, selective fms-like tyrosine kinase 3 (FLT3)/AXL inhibitor, gilteritinib (ASP2215), showed strong antileukemic activity at doses ≥80 mg/day in patients with FLT3 mutation-positive (FLT3^Mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML). This phase 3 trial was designed to compare the efficacy and safety of gilteritinib versus salvage chemotherapy in FLT3^Mut+ subjects with R/R AML.

Trial design

This phase 3, open-label randomized multicenter trial (NCT03182244) will enroll approximately 320 adult subjects (aged ≥18 years; Eastern Cooperative Oncology Group [ECOG] performance status ≤2) with FLT3^Mut+ R/R AML from ∼50 centers across China, Russia, Singapore, Thailand, and Malaysia. Subjects will be randomized (1:1) to receive 28-day cycles of once-daily oral gilteritinib (120 mg) or salvage chemotherapy. The salvage chemotherapy regimen will be selected by the investigator from the following predetermined options: LoDAC (intravenous [IV]/subcutaneous [SC] cytarabine 20 mg BID for 10 days), MEC (IV mitoxantrone 6 mg/m²/d plus IV etoposide 100 mg/m²/d plus IV cytarabine 1000 mg/m²/d, Days 1–5), or FLAG (granulocyte colony-stimulating factor SC/IV 300 μg/m²/d, Days 1–5; IV fludarabine 30 mg/m²/d, Days 2–6; IV cytarabine 2000 mg/m²/d, Days 2–6). Subjects receiving gilteritinib or LoDAC will continue treatment until a discontinuation criterion is met; those receiving MEC or FLAG will be assessed for response on or after Day 15 of Cycle 1 and will receive a second cycle of MEC/FLAG chemotherapy if bone marrow (BM) cellularity is ≥ 20% with ≥50% reduction in BM blasts. If BM cellularity is > 5% to < 20%, the decision to administer a second cycle of MEC/FLAG chemotherapy will be made by the investigator. The primary endpoint is overall survival; key secondary endpoints are event-free survival and complete remission rate. Safety endpoints include the incidence of adverse events, results from laboratory investigations and vital sign examinations, findings from electrocardiograms, and changes in ECOG performance status. A formal interim analysis is planned when approximately 50% of deaths have occurred.

Editorial acknowledgement

Writing and editorial assistance by Kalpana Vijayan, PhD (SuccinctChoice Medical Communications, Chicago, IL).

Clinical trial identification

NCT03182244.

Legal entity responsible for the study

Astellas Pharma, Inc.

Funding

Astellas Pharma, Inc.

Disclosure

S. Izuka, S. Yamada, E. Shima Rich, E. Bahceci: Employee: Astellas Pharma Inc. J. Hill: Employee: Astellas Pharma Inc.; Holds patents and stocks: Lagacept, LLC. All other authors have declared no conflicts of interest.

Background

Pts with newly diagnosed advanced OC are treated with cytoreductive surgery and platinum-based chemotherapy. Most relapse within the first 3 years and have further chemotherapy, but once relapsed are largely not curable. SOLO1 (NCT01844986) is the first Phase III trial to evaluate PARP inhibitor (olaparib [Lynparza®]) maintenance therapy after platinum-based chemotherapy in newly diagnosed advanced OC with a BRCAm.

Methods

SOLO1 is a randomized, controlled, double-blind trial. Eligible pts had newly diagnosed, FIGO stage III–IV, high-grade serous or endometrioid ovarian, primary peritoneal and/or fallopian tube cancer with a BRCAm, had received platinum-based chemotherapy and were in clinical complete or partial response. Pts were randomized 2:1 to olaparib tablets 300 mg bd or placebo. The primary endpoint was investigator-assessed progression-free survival (PFS; modified RECIST v1.1).

Results

Of 391 randomized pts, 260 received olaparib and 130 placebo (one pt did not receive placebo). Median follow-up was 41 months. Baseline characteristics were well balanced. Primary PFS analysis showed a significant 70% reduction in the risk of progression or death with olaparib versus placebo (Table). PFS sensitivity analyses, second PFS and time to first subsequent therapy or death support the primary analysis. Overall survival data are immature.Table: LBA3

Adverse events were mostly low grade. The most common grade ≥3 toxicities with olaparib were anaemia (22%) and neutropenia (8%). Olaparib dose reductions, interruptions and discontinuations occurred in 28%, 52% and 12%, respectively. There was no change from baseline in health-related quality of life scores with olaparib.

Conclusions

Maintenance olaparib led to a substantial, unprecedented improvement in PFS, with an estimated difference in median PFS for olaparib versus placebo of approximately 3 years.

Editorial acknowledgement

Gillian Keating, MBChB, from Mudskipper Business Ltd, funded by AstraZeneca and Merck & Co., Inc.

Clinical trial identification

NCT01844986, 26 August 2013.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

M. Friedlander: Personal fees for advisory boards: AZ and MSD. K. Moore: Consultancy: Tesaro, Genentech Roche, Clovis, Immunogen, VBL Therapeutics, Janssen (honorarium, ad board), AstraZeneca - honorarium, ad board (for agents not involved in the SOLO-1 study). N. Colombo: Honoraria: Genentech, Astra Zeneca, PharmaMar; Consulting or advisory role: Genentech, PharmaMar, AstraZeneca, Clovis Oncology, Pfizer, MSD, Tesaro; Research Funding AstraZeneca. G. Scambia: Fees for advisory role: Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro. A. Oaknin: Fees for advisory board: Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro; Travel/accommodation: Roche, AstraZeneca, PharmaMar. A. Floquet: Fees for advisory board: Astra Zeneca, Roche, Tesaro; Support travel: Roche. A. Leary: Ad boards: Clovis, AstraZeneca, Gamamabs, Pfizer, Gridstone; Travel costs: AstraZeneca; Preclinical research support: Merus, Gamamabs, Sanofi. G.S. Sonke: Institutional research support: AstraZeneca, Merck, Novartis, Roche. C. Gourley: Fees for advisory role: Roche, AstraZeneca, Tesaro, Nucana, Clovis, Foundation One; Lecture fees: AstraZeneca; Research funding (to my institution): Novartis, Aprea, AstraZeneca, Nucana, Tesaro. S. Banerjee: Research Funding AstraZeneca; Advisory boards: AstraZeneca, Tesaro, Clovis. A.M. Oza: Steering committees for trials: AstraZeneca, Clovis, Tesaro (all non-compensated); Honoraria: Intas Pharma. A. González-Martín: Grants as speaker/advisory board participants (last 36 months): AstraZeneca, Tesaro, Roche, Clovis, Pharmamar. C. Aghajanian: Consultancy: Tesaro, Cerulean, Bayer, VentiRx (honorarium, ad board); Mateon Therapeutics (honorarium steering committee meetings); Clovis (honorarium ad boards and steering committee meeting). W. Bradley: Fee for advisory role: Celsion E.S. Lowe, R. Bloomfield: Employee and stockholder: AstraZeneca. P. Disilvestro: Consulting fees: AstraZeneca and Tesaro (over last 2 years). All other authors have declared no conflicts of interest.

Background

Helicobacter pylori infection has a critical role in the pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. However, in patients who do not achieve a lymphoma regression or relapse following antibiotic therapy, a long-term outcome of the patients are scarce. We evaluated the long-term outcome of the patients who received irradiation or chemotherapies with relapsed or refractory gastric MALT lymphoma.

Methods

Between June 2000 and June 2017, a total of 29 H.pylori-positive gastric MALT lymphoma patients who received frontline H.pylori eradication regimen were included in this study. H.pylori-positive status was defined by positive results for the biopsy urease test and histology. They had all been diagnosed by endoscopy and had a complete staging including CT-scan and bone marrow biopsies. Patients received standard triple therapy for eradication of H.pylori and after treatment were sequentially followed-up with endoscopies performed to evaluate the response. Tumors that had resolved to complete remission (CR) score of GELA histologic grading system were considered treatment-responsive.

Results

During the follow-up periods 16 patients were refractory gastric MALT lymphoma, nine had probable minimal residual disease and four relapsed after the first-line antibiotics. Of these 29 patients, transformation into high-grade B-cell lymphoma did not occur. Among the non-responder and relapsed patients, three patients were subjected to a watch and wait, while 26 patients underwent second-line treatment including radiotherapy (n = 20), chemotherapy (n = 5), chemotherapy plus sequential radiotherapy (n = 1). Of the 20 patients treated with radiotherapy, the median dose to stomach was 3060 cGy. After radiotherapy a CR was achieved in 20 patients (100%). Among six patients who received chemotherapy, a CR was achieved in five patients and no change was in one. That patient was achieved CR after radiotherapy. Probabilities of freedom from treatment failure and overall survival after 10 years were 100% and 83%.

Conclusions

Outcome of patients with first-line H.pylori eradication failure followed by delayed chemotherapy and/or radiotherapy on indication was excellent.

Legal entity responsible for the study

Sung-Nam Lim.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.