No abstract

Nasopharyngeal carcinoma (NPC) is a unique disease endemic in Asia. It is etiologically linked to the Epstein-Barr virus and is both radio- and chemo-sensitive. While radiotherapy (RT) remains the primary treatment modality with high cure rates for early stage disease, systemic treatment forms an important integral component in the treatment of NPC, both in the non-metastatic as well as palliative setting. Presently, standard therapy in locally advanced NPC comprises conventional cytotoxic chemotherapy administered concurrently during RT. The role of induction chemotherapy and adjuvant chemotherapy remain to be well-defined. Further research strategies in non-metastatic disease will require better identification of patients with high risk disease, and determining the optimal sequence and combination of chemotherapeutic regimens. In metastatic disease, whilst chemotherapy remains the mainstay of care, resistance inevitably develops. Development of molecularly targeted therapies has not yielded much success to date, and further research has been focused on development of EBV-targeted strategies such as vaccination or administration of cytotoxic T-cells directed towards EBV, as well as evaluation of immune checkpoint inhibition approaches.

BackgroundAfatinib is an oral irreversible epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) indicated in first-line treatment of advanced EGFR-mutant (EGFRm+) non-small cell lung cancer (NSCLC). Dose dependent side effects can limit drug exposure, which may impact on extracranial and central nervous system (CNS) disease control.MethodsWe performed a retrospective study of 125 patients diagnosed with advanced EGFRm+ NSCLC treated with first-line afatinib at a tertiary Asian cancer center, exploring clinicopathological factors that may influence survival outcomes. Median progression free survival (PFS) was estimated using the Kaplan-Meier method. Comparison of PFS between subgroups of patients was done using log-rank tests and Cox proportional hazards models.ResultsOut of 125 patients, 62 (49.6%) started on 40 mg once daily (OD) afatinib, 61 (48.8%) on 30 mg OD and 1 (0.8%) on 20 mg OD. After median follow-up of 13.8 months from afatinib initiation, the observed response rate was 70.4% and median PFS 11.9 months (95% CI 10.3–19.3). 42 (33.6%) patients had baseline brain metastases (BM) and PFS of those who started on 40 mg OD (n = 17) vs. 30 mg OD (n = 25) was 13.3 months vs. 5.3 months (HR 0.39, 95% CI 0.15–0.99). BM+ patients who started on 40 mg had similar PFS to patients with no BM (13.3 months vs. 15.0 months; HR 0.79, 95% CI 0.34–1.80).ConclusionIn patients with advanced EGFRm+ NSCLC with BM+, initiating patients on afatinib 40 mg OD was associated with improved PFS compared to 30 mg OD, underscoring the potential importance of dose intensity in control of CNS disease.

Background: The effect of brain surgery on the clinical outcome of patients with nonsmall-cell lung cancer (NSCLC) and brain metastases (BM), particularly those with epidermal growth factor receptor (EGFR) mutations, has not been studied yet. We aimed to investigate whether brain surgery can improve the survival of patients with stage IV EGFR-mutant NSCLC who were treated with both first-line tyrosine kinase inhibitors (TKIs) and whole brain radiotherapy (WBRT). Methods: We searched the database for lung cancer patients diagnosed from 2011 to 2016 in one Asian university hospital. NSCLC patients who also had brain metastases diagnosed by either cytology or brain neuroimaging studies were identified. The treatments and clinical outcomes were reviewed. Overall survivals (OS) were estimated by Kaplan-Meier curves. Cox regression was performed. Results: Of 1394 NSCLC patients, we identified 100 patients with lung adenocarcinoma who had received both WBRT and TKIs. Most patients (60%) had been treated with brain surgery (BS þ RT group). All patients had TKIs. The median duration of TKIs use was 14.4 months (95% confidence interval (CI), 10.7-17.9). All patients had WBRT with a mean radiation dose of 37796748 cGy to their brain metastases. With a median follow-up of 25.6 months (95% CI, 18.6-35.7), the median survival after BM was 18.2 months (95% CI, 10.8-27.4) for patients who underwent brain surgery (TKI þ BS þ RT group) and 11.8 months (95% CI, 5.2-18) for patients who did not accept brain surgery (TKI þ RT group). The mean survival after BM were 21.9614.8 months and 15.6614.5 months for patients with and without brain surgery, respectively (P ¼ 0.026). Univariate analysis suggested that female gender, exon 19 mutation, brain surgery and solitary brain metastasis were favorable prognostic factors for longer survival. However, brain surgery failed to demonstrate its efficacy in multivariate analysis (P ¼ 0.134, hazard ratio ¼ 0.69).

Single-agent checkpoint inhibitor (CPI) activity in Epstein-Barr Virus (EBV) related nasopharyngeal carcinoma (NPC) is limited. Dual CPI shows increased activity in solid cancers. In this single-arm phase II trial (NCT03097939), 40 patients with recurrent/metastatic EBV-positive NPC who failed prior chemotherapy receive nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks. Primary outcome of best overall response rate (BOR) and secondary outcomes (progression-free survival [PFS], clinical benefit rate, adverse events, duration of response, time to progression, overall survival [OS]) are reported. The BOR is 38% with median PFS and OS of 5.3 and 19.5 months, respectively. This regimen is well-tolerated and treatment-related adverse events requiring discontinuation are low. Biomarker analysis shows no correlation of outcomes to PD-L1 expression or tumor mutation burden. While the BOR does not meet pre-planned estimates, patients with low plasma EBV-DNA titre (<7800 IU/ml) trend to better response and PFS. Deep immunophenotyping of pre- and on-treatment tumor biopsies demonstrate early activation of the adaptive immune response, with T-cell cytotoxicity seen in responders prior to any clinically evident response. Immune-subpopulation profiling also identifies specific PD-1 and CTLA-4 expressing CD8 subpopulations that predict for response to combined immune checkpoint blockade in NPC.