Targeted Oncology

Epidermal Growth Factor Receptor (EGFR)–Tyrosine Kinase Inhibitors (TKIs) Combined with Chemotherapy Delay Brain Metastasis in Patients with EGFR-Mutant Lung Adenocarcinoma Abstract Background Whether epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) combined with chemotherapy can delay the occurrence of brain metastasis (BM) is unclear. Objective This retrospective study aimed to evaluate whether EGFR–TKIs combined with chemotherapy can delay BM and decrease the incidence of BM as initial progression. Patients and Methods The data of 100 patients with EGFR-mutant advanced lung adenocarcinoma were retrospectively reviewed. The patients had no BM at initial diagnosis, and BM occurred during the treatment. Patients received EGFR–TKI only or EGFR–TKI combined with chemotherapy. Intracranial progression-free survival (iPFS), systemic progression-free survival (PFS), and overall survival (OS) were evaluated. Results The overall median OS was 39 months (95% confidence interval (CI), 35.6–42.4 months). The median OS of EGFR–TKI combined with chemotherapy and EGFR–TKI only are 41 months (95% CI 35.5–46.5 months) and 39 months (95% CI 36.8–41.2 months), respectively. Patients in the combination treatment group had longer PFS (16 vs. 10 months; P = 0.030) and iPFS (21 vs. 14 months; P = 0.026). Further, as initial progression, fewer patients developed BM in the combined treatment group compared with the EGFR–TKI-only group (30.6% vs. 52.9%, P = 0.002) with a hazard ratio of 0.64 (95% CI 0.43–0.96). After controlling for significant covariables in a multivariable model, the different treatment strategies were independently associated with improved iPFS. Conclusions In this retrospective analysis, EGFR–TKIs combined with chemotherapy could improve PFS. Further, the combined treatment could delay BM occurrence and decrease the incidence of BM as initial progression.

Authors' Reply to Yu: "Outcomes for Metastatic Colorectal Cancer Based on Microsatellite Instability: Results from the South Australian Metastatic Colorectal Cancer Registry"

Comment on: "Outcomes for Metastatic Colorectal Cancer Based on Microsatellite Instability: Results from the South Australian Metastatic Colorectal Cancer Registry"

Crizotinib in Chinese Patients with ROS1 -Rearranged Advanced Non‒Small-Cell Lung Cancer in Routine Clinical Practice Abstract Background Approximately 1–2% of patients with non‒small-cell lung cancer (NSCLC) harbor ROS1 rearrangements. Crizotinib, an oral small-molecule tyrosine kinase inhibitor (TKI) that targets anaplastic lymphoma kinase (ALK), MET, and ROS1, has shown marked antitumor activity in patients with ROS1-positive advanced NSCLC. Objective Our objective was to analyze the efficacy and safety of crizotinib treatment in Chinese patients with advanced NSCLC with ROS1 rearrangement in real-world clinical practice. Methods We included 35 patients with ROS1-positive NSCLC in this retrospective analysis. All received crizotinib 250 mg twice daily between March 2016 and April 2018 at the Fudan University Shanghai Cancer Center. All had histologically or cytologically confirmed locally advanced or metastatic NSCLC with ROS1 rearrangements, which were identified by fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, or next-generation sequencing. The main outcome measures were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events. Results The median age of the patients was 51.0 years; 23 (65.7%) were female and 28 (80.0%) were never smokers. All were diagnosed as having adenocarcinoma; eight patients (22.9%) had brain metastases at baseline. The ORR and DCR were 71.4% and 94.3%, respectively. The estimated median PFS was 11.0 months (95% confidence interval [CI] 7.8–14.2). The estimated median OS was 41.0 months (95% CI 22.5–59.5). Elevated transaminases (54.3%), vision disorder (25.7%), elevated blood creatinine (22.9%), diarrhea (20.0%), and vomiting (20.0%) were the most commonly reported adverse effects. Conclusion Crizotinib was effective and well tolerated in Chinese patients with ROS1-positive advanced NSCLC in real-world clinical practice. The progression sites and patterns, as well as treatments after first disease progression on crizotinib were diverse. Crizotinib beyond progressive disease and local therapy after failure of crizotinib treatment were feasible and effective in clinical practice.

The Urinary Microbiome and Anticancer Immunotherapy: The Potentially Hidden Role of Unculturable Microbes Abstract Several urinary disorders, including overactive bladder, urinary incontinence, and interstitial cystitis, are often characterized by negative urine cultures. The application of metagenomics (i.e., 16S rRNA microbial profiling or whole-genome shotgun sequencing) to urine samples has enabled the identification of previously undetected bacteria, contributing to the discovery and characterization of the urinary microbiome. The most frequent species isolated are Lactobacillus (15%), Corynebacterium (14.2%), Streptococcus (11.9%), Actinomyces (6.9%), and Staphylococcus (6.9%). Although several studies are emerging in this context, the role of urinary microbiota in the pathogenesis of infections and in tumor carcinogenesis remains unclear. Furthermore, data on the activity of gut microbiota in modulating sensitivity to immune checkpoint inhibitors in advanced cancer patients suggest that the influence of urinary microbiota on tumor response to anticancer therapy should also be investigated. Moreover, its possible relationship with tumor mutational burden, which is in turn correlated with response to immunotherapy, should be the focus of future studies. Of note, the effect of antibiotics on this complex scenario seems to deserve careful consideration.

Real-Life Efficacy of Osimertinib in Pretreated Octogenarian Patients with T790M-Mutated Advanced Non-small Cell Lung Cancer Abstract Background The resistance mutation T790M is reported in 50–60% of patients pretreated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Osimertinib has been approved in these patients, but data in octogenarians remain rare. Objective The objective of this retrospective analysis was to evaluate in real life the efficacy of osimertinib in a population of octogenarian patients. Methods This retrospective multicentric study included pretreated octogenarian patients with EGFR T790M-mutated advanced non-small cell lung cancer (NSCLC) in the setting of the French early access program for osimertinib. The primary endpoints were progression-free survival (PFS) and overall survival (OS) from osimertinib initiation. Results In total, 43 patients were included (mean age 84.6 years; women 90.7%: adenocarcinoma 100%; never smokers 90.5%; at osimertinib initiation: performance status ≥ 2, 42.4%; stage 4, 93.0%; brain metastases 16.3%). Patients received a median of two lines of treatment before osimertinib initiation, and all received first- or second-generation EGFR TKIs before osimertinib (first line in 79.1%). Osimertinib was used as a second-line treatment in 41.9% of cases and third line or more in 58.1%. Median PFS was 17.5 (95% confidence interval [CI] 12.2–19.0) months for the entire population: 20.6 (95% CI 18.8–not reached) months in patients with brain metastases and 16.7 (95% CI 10.4–18.9) months in patients without (p = 0.1). There was no significant difference for osimertinib treatment as second or third line or more (17.1 vs. 18.6 months, respectively). OS was 22.8 (95% CI 15.7–not reached) months from osimertinib initiation. Conclusion The efficacy of osimertinib as second-line treatment or more in octogenarian pretreated patients with EGFR T790M-mutated advanced NSCLC in a real-life setting was similar to that in randomized controlled trials.

Current Systemic Treatment Landscape of Advanced Gynecologic Malignancies Abstract Developments in systemic therapies beyond traditional cytotoxic chemotherapy have resulted in an unparalleled number of US Food and Drug Administration approvals in the past 5 years for ovarian, endometrial, and cervical cancer. In this review, we highlight registration trials leading to recent Food and Drug Administration approvals for targeted systemic therapies in advanced gynecologic malignancies, encompassing three classes of agents: the antiangiogenic anti-vascular endothelial growth factor antibody bevacizumab in ovarian and cervical cancer, poly (ADP-ribose) polymerase inhibitors in ovarian cancer, and the immune checkpoint inhibitor pembrolizumab in cervical and endometrial cancer. The addition of bevacizumab to chemotherapy has been approved in frontline and relapsed advanced ovarian cancer, in both platinum-resistant and platinum-sensitive settings. Three poly (ADP-ribose) polymerase inhibitors are approved for women with ovarian cancer. Olaparib and rucaparib are utilized in recurrent germline or somatic BRCA mutated ovarian cancer. Along with a third poly (ADP-ribose) polymerase inhibitor, niraparib, they are also Food and Drug Administration approved as maintenance therapy regardless of BRCA mutation status for patients with recurrent ovarian cancer in complete or partial response to platinum-based chemotherapy. More recently, olaparib was approved as maintenance therapy for BRCA mutated ovarian cancer following first-line platinum-based chemotherapy. Pembrolizumab has been approved for relapsed cervical cancer with programmed death ligand 1 positivity and relapsed solid tumors with mismatch repair deficiency, which applies to 30% of endometrial cancers. Together, these therapies represent the advent of personalized medicine in gynecologic malignancies. Additional information is required to determine cost-effective strategies for incorporating these therapies and rational means of sequencing these agents.

Efficacy of Crizotinib for Advanced ALK -Rearranged Non-Small-Cell Lung Cancer Patients with Brain Metastasis: A Multicenter, Retrospective Study in China Abstract Background The efficacy of crizotinib for anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) patients with brain metastasis is controversial. Real-world research data are needed as further evidence. Objective We conducted a multicenter, retrospective study to explore how crizotinib affects the control of brain metastasis and the survival outcomes among Chinese patients. Patients and Methods We reviewed the medical records of unselected ALK-rearranged NSCLC patients treated with crizotinib at five hospitals in China from January 1, 2013 to November 30, 2017. Patients developing brain metastasis either before or during crizotinib treatment were included. Survival outcomes were analyzed by the Kaplan–Meier method, and prognostic factors were analyzed by multivariate Cox regression. Results A total of 174 patients were included in the analysis; 95 of these patients had baseline brain metastasis, while 79 patients developed brain metastasis during crizotinib treatment. Among patients with baseline brain metastasis, the median intracranial time to progression was 19.3 months (95% confidence interval [CI] 12.5–26.2) and the median overall survival (OS) was 53.4 months (95% CI not reached). A total of 135 patients experienced intracranial progression, and 94 of these patients continued crizotinib beyond progressive disease (CBPD). There was no significant difference in the median OS between patients with CBPD and without CBPD (48.3 months vs 53.4 months; p = 0.296). Conclusions ALK-rearranged advanced NSCLC patients with baseline brain metastasis can still achieve OS benefits from crizotinib treatment. However, patients with intracranial progression may not obtain a long-term survival benefit from continuation of CBPD.

Clinical Modality of Resistance and Subsequent Management of Patients with Advanced Non-small Cell Lung Cancer Failing Treatment with Osimertinib Abstract Background The third-generation epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) osimertinib has become the standard treatment for patients with pretreated EGFR-mutated non-small cell lung cancer (NSCLC) who acquire the T790M resistance mutation. However, no standard treatment after osimertinib failure has been established. Objective This study was undertaken to explore the clinical resistance modality upon failure of osimertinib therapy and to assess post-progression treatments in a real-world setting. Patients and Methods Medical data were retrospectively collected in our cancer center of patients with advanced NSCLC treated between 1 March 2017 and 1 July 2018, and who developed resistance to osimertinib. Results A total of 65 patients were analyzed. Clinical resistance modality varied among patients: 15 (23.1%) with local progression, 29 (44.6%) with gradual progression, and 21 (32.3%) with dramatic progression. Most patients experienced intrathoracic progression only (40/65, 61.5%), while ten (15.4%) cases presented intracranial failure only. Upon progressive disease, 20 patients (30.8%) received subsequent chemotherapy, and showed a trend for longer median overall survival (OS) than in those receiving a non-chemotherapy regimen (25.0 vs. 11.8 months, p = 0.106). Thirty-nine patients (60.0%) continued osimertinib beyond progression with a median post-progression treatment duration of 4.1 months. No significant difference in median OS was seen between patients who continued osimertinib and those who discontinued osimertinib (18.9 vs. 15.1 months, p = 0.802). In subgroup analyses, OS was improved in patients who experienced dramatic progression and were treated with chemotherapy, but data were immature for patients with local or gradual progression. Conclusions Chemotherapy could be an effective option after osimertinib failure in unselected patients.

MINOAS: A Single-arm Translational Phase II Trial of FOLFIRI Plus Aflibercept as First-line Therapy in Unresectable, Metastatic Colorectal Cancer Abstract Background FOLFIRI/aflibercept is approved as a second-line treatment in metastatic colorectal cancer (mCRC) but there are limited data for its use as a first-line treatment. Objective To investigate the activity and safety of first-line FOLFIRI/aflibercept in mCRC, as well as to prospectively evaluate biomarkers of early response to treatment. Patients and methods MINOAS was a phase II trial that aimed to evaluate the activity and toxicity of first-line FOLFIRI/aflibercept in mCRC. The primary endpoint was objective response rate (ORR). The secondary endpoints were toxicity, progression-free survival (PFS), overall survival (OS), and the evaluation of CEACAM-positive circulating tumor cells (CTC) and diffusion-weighted (DW)-MRI as biomarkers. Results Thirty-one patients were enrolled and 259 chemotherapy cycles were administered. At the time of the preplanned interim analysis, all patients had discontinued treatment and the ORR was 61.3%, crossing the activity threshold for trial discontinuation. Median PFS was 8.4 months (95% CI 7.8–9.0). Median OS had not been reached. There was one toxic death due to sepsis; grade 3/4 adverse events included neutropenia (n = 5), diarrhea (n = 6), hypertension (n = 4), asthenia (n = 3), proteinuria (n = 1), and bowel perforation (n = 1). Retaining CTC-negative status predicted better OS compared to continuous detection of CTCs (p = 0.015). Early decrease of the apparent diffusion coefficient (ADC) in DW-MRI was associated with an objective response. Conclusion The activity and safety of first-line FOLFIRI/aflibercept merit further evaluation in randomized studies. Clinicaltrials.gov registration number NCT02624726.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com