L. Xing

Predictive biomarkers in PD-1/PD-L1 checkpoint blockade immunotherapy.

Checkpoint blockades turn on a new paradigm shift in immunotherapy for cancer. Remarkable clinical efficacy, durable response and low toxicity of programmed death 1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint blockades have been observed in various malignancies. However, a lot of cancer patients failed to respond to the PD-1/PD-L1 checkpoint blockades. It is crucial to identify a biomarker to predict the response to checkpoint blockades. The overexpression of PD-L1 is an important and widely-explored predictive biomarker for the response to PD-1/PD-L1 antibodies. However PD-L1 staining cannot be used to accurately select patients for PD-1/PD-L1 pathway blockade due to the low prediction accuracy and dynamic changes. Tumor-infiltrating immune cells and molecules in the tumor microenvironment, or along with PD-L1 expression, may be important in predicting clinical benefits of PD-1/PD-L1 checkpoint blockades. Gene analysis has proven to be new approach for judging the potential clinical benefit of immune checkpoint inhibitors, such as mutational landscape and mismatch-repair deficiency. Further preclinical and clinical studies are necessary to carry out before its application in clinical practice. Challenges should be overcome to identify patients accurately who will benefit from PD-1/PD-L1 checkpoint blockades. In this review, we focus on the predictive biomarkers for checkpoint blockades of PD-1/PD-L1 pathway.

NONINVASIVE EVALUATION OF MICROSCOPIC TUMOR EXTENSIONS USING STANDARDIZED UPTAKE VALUE AND METABOLIC TUMOR VOLUME IN NON-SMALL-CELL LUNG CANCER

PURPOSE To prospectively evaluate whether maximal microscopic extensions (MEmax) correlate with maximal standardized uptake value (SUVmax) and metabolic tumor volume (MTV) at 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) images in non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS Thirty-nine patients with Stage I-IIIA NSCLC underwent surgery after FDG-PET/CT scanning. SUVmax and MTV were calculated on the PET/CT images. The maximum linear distance from the tumor margin to the farthest extent of the tumor in every dimension was measured at the tumor section. The correlations among MEmax, SUVmax, MTV and other clinical pathologic parameters were analyzed. RESULTS MEmax for all patients had a significant correlation with SUVmax (r = 0.777, p = 0.008) and MTV (r = 0.724, p < 0.001). When expressed in terms of the probability of covering ME with respect to a given margin, we suggested that margins of 1.93 mm, 3.90 mm, and 9.60 mm for SUVmax ≤ 5, 5-10, and >10 added to the gross tumor volume would be adequate to cover 95% of ME. CONCLUSIONS This study demonstrated that tumors with high SUVmax and MTV have more MEmax and would therefore require more margin expansion from gross tumor volume to clinical target volume. FDG-PET/CT, especially for SUVmax, is promising and effective and merits additional study in noninvasive delimiting of the clinical target volume margin for NSCLC.

PET/CT imaging-guided dose painting in radiation therapy

Application of functional imaging to radiotherapy (RT) is a rapidly expanding field with the development of new modalities and techniques. Functional imaging of PET in conjunction with RT provides new avenues towards the clinical application of dose painting - a new RT strategy delivering optimized dose redistribution according to the functional imaging information to further improve tumour control. Two prototypical strategies of dose painting are reviewed: dose painting by contours (DPBC) and dose painting by numbers (DPBN). DPBN set a linear correlation of the boost dose and image intensity of this same voxel while homogeneous dose is given to the subvolume contoured by a threshold created in PET images in DPBC. Both comply with strict organs at risk (OAR) constraints and are alternatives for boosting subvolumes in clinical practice. This review focuses on the rationale, target validation, dose prescription verification and evaluation and recent clinical achievements in the field of integrating PET imaging into RT treatment planning. Further research is necessary in order to investigate unresolved problems in its routine clinical application thoroughly.

PD-1/PD-L1 checkpoint blockades in non-small cell lung cancer: New development and challenges

PD-1/PD-L1 checkpoint blockades have dramatically changed the landscape for second-line treatment of non-small cell lung cancer (NSCLC). Based on the promising results of Keynote-024 presented so far, pembrolizumab has been approved as first-line treatment for advanced PD-L1 positive NSCLC patients. However, overall response rate (ORR) is limited to PD-1/PD-L1 checkpoint blockades when used as single agent. Combining with chemotherapy, anti-CTLA-4 antibodies, targeted therapy, radiotherapy or other treatment options is perceived as an appealing method aimed at achieving higher efficacy. There are many clinical trials on going or finished assessing the efficacy and safety of the PD-1/PD-L1 blockades alone or combining with other approaches in first-line or second-line treatments. A lot of challenges need to be overcome before PD-1/PD-L1 checkpoint blockades are widely used in the patients with NSCLC including the identification of optimal combination, treatment-related adverse effects, the high cost and lack of effective predictive markers. In this review, we focus on outlining current clinical trials and challenges for future research of PD-1/PD-L1 pathway checkpoint blockades in NSCLC.

Interactions between EGFR and PD-1/PD-L1 pathway: Implications for treatment of NSCLC

Immune checkpoint inhibitors targeting the programmed cell death receptor/ligand 1 (PD-1/PD-L1) pathway displayed striking and durable clinical responses in patients with non-small-cell lung cancer (NSCLC). However, it is still undefined about the efficacy of PD-1/PD-L1 inhibitors in NSCLC patients with EGFR activating mutations. Preclinical studies indicate the immune modulatory effect of EGFR signaling by regulating expression of MHC I/II and PD-L1 on tumor cells and activity of lymphocytes. Thus, it might be practicable for the use of PD-1/PD-L1 inhibitors as monotherapy or combined with EGFR-TKIs in patients with EGFR activating mutations. In this review, we discussed the regulation effect of EGFR signaling on PD-1/PD-L1 pathway and the potential mechanisms behind combing EGFR-TKIs with PD-1/PD-L1 inhibitors. We also reviewed current available data on PD-1/PD-L1 inhibitors as monotherapy or combined with EGFR-TKIs in NSCLC with EGFR activating mutations, and explored possible factors influence its efficacy, which would be important considerations for future clinical trial designs.

Osimertinib (AZD9291) increases radio‑sensitivity in EGFR T790M non‑small cell lung cancer

Osimertinib (AZD9291) is a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has demonstrated significant clinical benefits in patients with EGFR-sensitizing mutations or the T790M mutation. However, the potential therapeutic effect of osimertinib combined with ionizing irradiation (IR) is not well understood. The present study investigated treatment with osimertinib combined with IR in EGFR T790M non-small cell lung cancer (NCI-H1975) in vitro and in vivo. The results revealed that osimertinib inhibited proliferation and clonogenic survival following irradiation, decreased G2/M phase arrest in irradiated cells, and delayed DNA damage repair in a concentration- and time-dependent manner. Furthermore, osimertinib alone or in combination with IR, blocked the phosphorylation of EGFR (Tyr1068/Tyr1173), protein kinase B and extracellular signal-regulated kinase. Osimertinib also enhanced the antitumor activity of IR in tumor-bearing nude mice. The results of the present study indicated that osimertinib has therapeutic potential as a radiation-sensitizer in lung cancer cells harboring the EGFR T790M mutation, providing a rationale for clinically combining osimertinib with irradiation in EGFR T790M non-small cell lung cancer.