Befotertinib (D-0316) is a novel, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). This study aimed to evaluate the efficacy and safety of befotertinib in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that had EGFR T790M mutation after prior first- or second-generation EGFR TKIs.

ROS1 fusions (ROS1+) are enriched in 1-2% of non-small cell lung cancer (NSCLC) cases. SAF-189s is a novel, next-generation ALK/ROS1 inhibitor which overcomes multiple resistance mutations. We explored the efficacy and safety of SAF-189s in phase (Ph) 2 study in patients (pts) with ROS1 fusion NSCLC, with or without ROS1 inhibitor treatment.

Lorlatinib, a third-generation inhibitor of anaplastic lymphoma kinase (ALK), was shown in a global Phase 2 study to have potent overall and intracranial (IC) anti-tumor activity in patients with ALK-positive advanced non-small cell lung cancer (NSCLC) after progression on first- and/or second-generation ALK inhibitors (NCT01970865). Here we report primary data from a multicenter Phase 2 study conducted in China that investigated lorlatinib in ALK inhibitor-treated patients with ALK-positive NSCLC (NCT03909971).

Background: Anti-PD-1/L1 antibodies could be an optional therapy for EGFR-TKI-resistant non-small cell lung cancer (NSCLC) patients with EGFR mutation. However, little is known about PD-L1 expression in advanced NSCLC patients with the T790M-positive EGFR mutation, as well as the changes induced by osimertinib treatment. Methods: From July 2017 to February 2020, 63 advanced NSCLC patients with T790M-positive EGFR mutation were screened and enrolled in the study to receive osimertinib treatment at 80 mg orally once daily. PD-L1 expression on tumor cells at baseline and after progression was evaluated by immunohistochemistry with VENTANA PD-L1 (SP263) assay. Results: The mean age of the 63 enrolled patients was 61.4±10.77 years, including 29 males (46.0%) and 34 females (54.0%). All patients were Chinese and most of them were advanced NSCLC patients with adenocarcinoma (60/63, 95.2%). The osimertinib treatment duration and follow-up time ranged from 6 to 126 weeks. At baseline, the positive rate of PD-L1 expression on tumor cells with different cut-off points (≥1%, ≥25%, ≥50%) was 34.1% (14/41), 4.9% (2/41), and 4.9% (2/41), respectively. After progression, among 12 samples tested for PD-L1 expression, 41.7% (5/12), 16.7% (2/12) and 8.3% (1/12) were PD-L1 positive on tumor cells with cut-off points at 1%, 25% and 50%, respectively. Ten patients with samples tested both at baseline and after progression were analyzed for the change of PD-L1 expression. The mean change in the positive rate of PD-L1 expression from baseline to progression was 9.05% (95% CI: -4.895%, -22.995%, P = 0.0625, n = 10). Among these 10 patients, PD-L1 expression on tumor cells were all negative (< 1%) at baseline, but 50%≥5/10, ≥ 1% expression), 20%≥2/10, ≥25%) and 10%≥1/10, ≥50%≥of them were positive after progression. Conclusions: We observed that PD-L1 expression on tumor cells tended to increase after osimertinib treatment in advanced EGFR T790M-positive NSCLC patients, which may provide clues for optimization of subsequent anti-PD-1/L1 treatment. The effect of osimertinib treatment on PD-L1 expression in EGFR T790M-positive NSCLC patients warrants further validation in study with a larger population. Legal entity responsible for the study: Guangdong Association of Clinical Trails (GACT) Chinese Thoracic Oncology Group (CTONG). Funding: AstraZeneca. Disclosure: All authors have declared no conflicts of interest.

Neurotrophic receptor kinase (NTRK) fusions involving NTRK1, NTRK2 and NTRK3 are oncogenic drivers in a broad range of adult and pediatric tumor types. Despite of their low frequencies among various tumor populations, NTRK fusions have been recognized as actionable biomarkers to predict response to tropomyosin receptor kinase (TRK) inhibitors, making their routine detection an evolving clinical priority. In this study, next-generation sequencing (NGS) was applied to explore NTRK fusions in Chinese lung carcinoma patients, and to explore the relationships between NTRK fusions and clinicopathological features.

In KEYNOTE-010, pembro improved OS vs doce as 2L+ therapy for advanced NSCLC with PD-L1 TPS ≥1% and ≥50%. KEYNOTE-010 did not enroll any pts from mainland China, which has high NSCLC mortality. KEYNOTE-033 (NCT02864394) evaluates pembro vs doce in pts with previously treated advanced NSCLC with PD-L1 TPS ≥1%, with most pts enrolled in mainland China. Eligible pts (≥18 y) were randomized to pembro 2 mg/kg Q3W (35 cycles) or doce 75 mg/m2 Q3W (per local standard of care), stratified by TPS (≥50% vs 1–49%). Response was assessed Q9W per RECIST v1.1 by BICR. PD-L1 expression was assessed centrally (PD-L1 IHC 22C3 pharmDx assay). OS and PFS (primary objectives) were evaluated sequentially using stratified log-rank tests, first in pts with TPS ≥50% and then in pts with TPS ≥1% (1-sided α=0.025). 425 pts were enrolled. At data cutoff (Sep 9, 2019), median follow-up was 18.8 (range, 0.2-38.8) mo, and 291 (68%) pts had died. Pembro numerically improved OS in all groups analyzed, but did not achieve predefined statistical significance in pts with PD-L1 TPS ≥50% (Table); thus, sequential testing of OS and PFS ceased. HR for OS in TPS ≥1% pts from mainland China (n=311) was 0.68 (95% CI, 0.51–0.89). In all treated pts, incidence of treatment-related AEs was lower with pembro vs doce (any grade, 70% vs 88%; grade 3-5, 11% vs 47%).Table:PembroDocePD-L1 TPS ≥50%N=114N=113OSMedian (95% CI), mo12.3 (10.0-16.3)10.9 (8.3-13.1)HR (95% CI)0.83 (0.61-1.14)P0.1276PFSMedian (95% CI), mo4.0 (2.1-8.0)2.5 (2.1-4.2)HR (95% CI)0.76 (0.54-1.07)ORR% (95% CI)28.1 (20.1-37.3)7.1 (3.1-13.5)PD-L1 TPS ≥1%N=213N=212OSMedian (95% CI), mo12.9 (10.3-16.5)10.6 (8.7-12.5)HR (95% CI)0.75 (0.60-0.95)PFSMedian (95% CI), mo3.3 (2.1-4.1)3.0 (2.3-4.0)HR (95% CI)0.84 (0.66-1.08)ORR% (95% CI)20.7 (15.4-26.7)5.7 (3.0-9.7) Open table in a new tab While pembro did not meet statistical significance for OS in pts with PD-L1 TPS ≥50%, HRs for OS and PFS numerically favored pembro and ORR was higher with pembro in both the PD-L1 TPS ≥50% and ≥1% groups. Toxicity was consistent with the established pembro safety profile. These data support the value of pembro for previously treated advanced NSCLC in China.

Colorectal cancer (CRC) is one of the most prevalent solid cancers, and its incidence is increasing in young patients worldwide. So far, knowledge of adolescents and young adults (AYAs) with CRC has been still limited. In this study, we aimed to elucidate the unique genomic and clinical characteristics in AYAs with CRC. A total of 81 Chinese AYAs (<= 35 years old) with CRC were enrolled in this study. Targeted deep sequencing with 450 cancer-associated genes was performed on formalin-fixed, paraffin-embedded (FFPE) tumour samples and matched blood samples. Comprehensive genomic profiling was performed; this included analysis of single nucleotide variants (SNV), short and long insertions and deletions (Indel), and copy number variations (CNV). Gene fusions were analysed by OrigiFus, an in-house developed method. Our study showed that 98.8% (80/81) of AYAs harboured at least one genomic alteration. The median tumour mutational burden (TMB) was 5.4 muts/Mb (ranged from 0.6-525.6 muts/Mb) and the median age was 31 yrs (ranged from 17-35 yrs). Among the total 81 AYAs, 60 (74.1%) had advanced CRC (stage > II) and 14 (17.3%) showed microsatellite instability (MSI-H). The most frequent alterations were detected in TP53 (72.8%), KRAS (45.7%), SMAD4 (39.5%), APC (39.5%) and PIK3CA (32.1%). Alterations of APC were decreased compared to previous studies (39.5% vs 71%) (Liang Huang et al., Journal of Clinical Oncology 2020 38:4_suppl, 222-222) while an opposite trend was found in SMAD4 (39.5% vs 22%) and PIK3CA (32.1% vs 21%). Alterations of TP53 (84.1% vs 28.6%, P < 0.001) and SMAD4 (47.6% vs 14.3%, P = 0.03) were significantly higher in the microsatellite stable (MSS) group compared to MSI-H group. In contrast, alterations of APC (85.7% vs 28.6%, P < 0.001) and PIK3CA (78.6% vs 22.2%, P < 0.001) were significantly higher in the MSI-H group compared to the MSS group. Alterations in PIK3CA were identified more frequently in early stage CRC(stage <= II) compared to advanced stages (57.1% vs 25%, P = 0.04). Our study revealed that AYAs with CRC had distinct genomic features with high levels of SMAD4 and PIK3CA alterations and lower levels of APC alterations, which is different to what is observed in adult CRC patients. Further in-depth analyses of the genomic landscape of AYAs with CRC are needed to reveal distinct therapeutic avenues.

Background PD-L1 immunohistochemistry (IHC) data in China was less reported. We systematically investigated PD-L1 IHC data of Chinese patients generated by Origimed. Methods PD-L1 was stained using IHC on cancer samples from 2060 Chinese patients in Origimed since 2017. Written informed consent was obtained from each patient. IHC staining was performed on FFPE tissue sections using anti-PD-L1 antibody 28-8. Tumor Proportion Score (TPS) was applied on all the samples. We investigated PD-L1 TPS in lung adenocarcinoma (n = 893), lung squamous carcinoma (n = 172), liver cancer (n = 404), esophageal cancer (n = 186), colorectal cancer (n = 166), pancreatic cancer (n = 136) and gastric cancer (n = 103). We then further applied PD-L1 combined positive score (CPS) on the 103 gastric cancer samples. All the slides were reviewed by the same senior pathologist. 95% confidence interval (CI) was obtained by bootstrap. Information entropy (Shannon’s formula) was measured in natural units. Results The highest proportion of PD-L1 TPS > = 1% was observed in lung squamous carcinoma (49%; 95% CI: [43%, 59%]), followed by lung adenocarcinoma (25%; 95% CI: [22%, 28%]), liver cancer (14%; 95% CI: [11%, 18%]), esophageal cancer (12%; 95% CI: [8.1%, 17%]), pancreatic cancer (11%; 95% CI: [5.9%, 16%]), gastric cancer (7%; 95% CI: [1.9%, 12%]) and colorectal cancer (4%; 95% CI: [1.2%, 6.6%]). The proportion of PD-L1 CPS > = 1 for gastric cancer was 17% (95% CI: [9.7%, 24%]). In gastric cancer, information entropy of TPS and CPS was 0.40 and 0.78, respectively. Conclusions The proportion of PD-L1 TPS > = 1% in Chinese lung squamous cell carcinoma (49%) was much higher than that in lung adenocarcinoma (25%). PD-L1 CPS contained more information than TPS in gastric cancer. Thus, we recommend applying CPS to gastric cancer in China. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure X. Pan: Full / Part-time employment: Origimed. Y. Dai: Full / Part-time employment: Origimed. D. Chen: Full / Part-time employment: Origimed. K. Wang: Full / Part-time employment: Origimed. X. Dong: Full / Part-time employment: Origimed. All other authors have declared no conflicts of interest.

RET is known as a driver gene which accounts for 1-2% in NSCLC. Recently, RET inhibitors such as LOXO-292 and BLU-667 demonstrated promising efficacy in NSCLC and medullary thyroid cancer. The landscape of RET alterations of the Chinese NSCLC population will be explored in this study. FFPE tumor and matched blood samples of 3433 Chinese NSCLC patients were collected for performing next-generation sequencing (NGS) based targeted panel sequencing. The genomic variants including single nucleotide variations, indels, copy number alterations and gene rearrangements were analyzed. Tumor mutational burden (TMB) and microsatellite instability (MSI) status were calculated and assessed by NGS algorithms. The patients with RET alterations, including 61 males and 57 females with a median age of 59.5 years, were identified in approximately 3.4% (118/3433) of the Chinese NSCLC cohort. In this study, 58 out of 118 (1.7%) patients, including 21 males and 37 females with a median age of 58 years, harbored RET rearrangements, which is slightly higher than the published data of MSKCC (1.2%). The partner genes of RET rearrangements were identified by NGS, including KIF5B (38/58), CCDC6 (6/58), and other genes (14/58). TP53 was the most common compound gene with RET rearrangements. Two co-existing EGFR mutations, L858R and L861Q, were identified in 2 RET rearrangement patients without previous treatments. Harbored alterations in the cell cycle pathway and in the PI3K/mTOR pathway were found in 15.5% (9/58) and 12.1% (7/58) of patients, respectively. In addition, 8 patients with RET rearrangements had no other co-occurring common cancer gene mutations. Meanwhile, 56 (1.6%) patients carried RET mutations and 5 (0.2%) patients presented RET amplifications. The median TMB of patients with RET alteration was 4.6 muts/Mb, which was exactly the same as all the 3433 patients (4.6 muts/Mb). Interestingly, patients with RET rearrangements had lower TMB (2.3 muts/Mb, 0-16.2 muts/Mb). All patients with RET alternations were microsatellite stable (MSS). This is the first study to reveal RET genomic profiling in a large Chinese NSCLC cohort. RET rearrangements were found in 1.7% of Chinese NSCLC. Besides the most common partner genes, 14 RET rearrangements (24%) with uncommon or novel partner genes were identified by NGS. TMB of the patients with RET rearrangements was relatively lower.

Very recently, it was suggested that pembrolizumab monotherapy can be extended as first-line therapy to patients (pts) with locally advanced or metastatic non-small-cell lung cancer (NSCLC) without sensitizing EGFR or ALK alterations and with low PD-L1 Tumor Proportion Score (TPS). Then screening the subset of pts with PD-L1 TPS ≥1% from all the EGFR-, ALK- locally advanced or metastatic NSCLC pts became important. However, less was known about the percentage of this subset in China. We investigated this percentage taking advantage of the retrospective NSCLC cohort collected by Origimed. The Origimed-based NSCLC cohort was a retrospective cohort consisted of more than one thousand Chinese NSCLC pts who underwent both NGS panel sequencing and PD-L1 immunohistochemistry (IHC) in a College of American Pathologists (CAP) certified and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory during the year 2017 and 2018. Antibodies used in the PD-L1 IHC assay included 22C3 and 28-8. TPS was applied. All the slides were reviewed by the same senior pathologist. All the EGFR and ALK alterations were manually reviewed in Integrated Genomics Viewer for confirmation. Stage III or IV at diagnosis was used as an approximation to the criteria "locally advanced or metastatic". Excluding sensitizing EGFR/ALK alteration carriers, there were totally 27 locally advanced or metastatic NSCLC pts whose 22C3 PD-L1 TPS were available and 202 locally advanced or metastatic NSCLC pts whose 28-8 PD-L1 TPS were available in the cohort. Among them, 55.6% (15/27) 22C3 stained samples had TPS ≥1%, and 40.6% (82/202) 28-8 stained samples had TPS ≥1%. More than 40% of locally advanced or metastatic NSCLC pts without EGFR/ALK alterations have PD-L1 TPS ≥1% in China. These pts may benefit from first-line pembrolizumab monotherapy.

EGFR mutations are more prevalent in lung adenocarcinoma compared with other non-small cell lung cancer and are more prevalent in East Asians compared with the other populations. At the same time, we observed lower PD-L1 Tumor Proportion Score (TPS) in Chinese lung adenocarcinoma patients (pts) compared with that in Chinese lung squamous cell carcinoma pts and we also observed the proportion of PD-L1 positive (TPS ≥ 1%) in Chinese lung adenocarcinoma pts was lower than that in other multicenter cohorts. Then we hypothesize that the higher prevalence of EGFR mutations in Chinese lung adenocarcinoma pts correlates with lower PD-L1 expression. The Origimed-based lung adenocarcinoma cohort was a retrospective cohort consisted of more than one thousand Chinese lung adenocarcinoma pts who underwent both NGS panel sequencing and PD-L1 immunohistochemistry (IHC) in a College of American Pathologists (CAP) certified and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory during the year 2017 and 2018. Antibodies used in the PD-L1 IHC assay included 28-8 (sample size = 883) and 22C3 (sample size = 158). Tumor Proportion Score (TPS) was applied. All the slides were reviewed by the same senior pathologist. All the EGFR mutations were manually reviewed in Integrated Genomics Viewer for confirmation. After confirmation, each pts was assigned to EGFR positive group or EGFR negative group. Fisher' s exact test and Student' s t-test were applied. For antibody 28-8, PD-L1 IHC was positive (TPS ≥1%) in 18% (66/370) EGFR positive pts and was positive in 35% (180/513) EGFR negative pts (fisher exact test p value = 1.6e-5). For antibody 22C3, PD-L1 IHC was positive (TPS ≥1%) in 14% (9/64) EGFR positive pts and was positive in 45% (42/94) EGFR negative pts (fisher exact test p value = 3.8e-3). And we observed a significantly lower PD-L1 TPS in EGFR positive pts for both antibodies (t-test p value = 3.5e-11 for PD-L1 antibody 28-8; t-test p value = 6.0e-5 for PD-L1 antibody 22C3). The observation demonstrated that lower PD-L1 TPS in Chinese Lung Adenocarcinoma pts was significantly correlated with East-Asian-specific high prevalence of EGFR mutations. The observation reassured that EGFR mutation status should be examined simultaneously with PD-L1 IHC in lung adenocarcinoma pts because it was a confounding factor for predicting immunotherapy outcome using PD-L1 TPS. The observation partly explained the generally higher PD-L1 TPS in Chinese lung squamous carcinoma pts compared with that in Chinese lung adenocarcinoma pts.

EGFR mutations are more prevalent in lung adenocarcinoma compared with other non-small cell lung cancer and are more prevalent in East Asians compared with the other populations. At the same time, we observed lower PD-L1 Tumor Proportion Score (TPS) in Chinese lung adenocarcinoma patients (pts) compared with that in Chinese lung squamous cell carcinoma pts and we also observed the proportion of PD-L1 positive (TPS >= 1%) in Chinese lung adenocarcinoma pts was lower than that in other multicenter cohorts. Then we hypothesize that the higher prevalence of EGFR mutations in Chinese lung adenocarcinoma pts correlates with lower PD-L1 expression. The Origimed-based lung adenocarcinoma cohort was a retrospective cohort consisted of more than one thousand Chinese lung adenocarcinoma pts who underwent both NGS panel sequencing and PD-L1 immunohistochemistry (IHC) in a College of American Pathologists (CAP) certified and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory during the year 2017 and 2018. Antibodies used in the PD-L1 IHC assay included 28-8 (sample size = 883) and 22C3 (sample size = 158). Tumor Proportion Score (TPS) was applied. All the slides were reviewed by the same senior pathologist. All the EGFR mutations were manually reviewed in Integrated Genomics Viewer for confirmation. After confirmation, each pts was assigned to EGFR positive group or EGFR negative group. Fisher' s exact test and Student' s t-test were applied. For antibody 28-8, PD-L1 IHC was positive (TPS ≥1%) in 18% (66/370) EGFR positive pts and was positive in 35% (180/513) EGFR negative pts (fisher exact test p value = 1.6e-5). For antibody 22C3, PD-L1 IHC was positive (TPS ≥1%) in 14% (9/64) EGFR positive pts and was positive in 45% (42/94) EGFR negative pts (fisher exact test p value = 3.8e-3). And we observed a significantly lower PD-L1 TPS in EGFR positive pts for both antibodies (t-test p value = 3.5e-11 for PD-L1 antibody 28-8; t-test p value = 6.0e-5 for PD-L1 antibody 22C3). The observation demonstrated that lower PD-L1 TPS in Chinese Lung Adenocarcinoma pts was significantly correlated with East-Asian-specific high prevalence of EGFR mutations. The observation reassured that EGFR mutation status should be examined simultaneously with PD-L1 IHC in lung adenocarcinoma pts because it was a confounding factor for predicting immunotherapy outcome using PD-L1 TPS. The observation partly explained the generally higher PD-L1 TPS in Chinese lung squamous carcinoma pts compared with that in Chinese lung adenocarcinoma pts.

EGFR mutation is one of the most common driver gene mutations in non-small cell lung cancer (NSCLC) patients, especially in adenocarcinoma. Increasing numbers of rare alterations of EGFR such as kinase domain duplication and fusion have been identified with the clinical applications of next generation sequencing (NGS). However, co-occurring genomic alterations of EGFR have not been fully understood in Chinese lung adenocarcinoma patients. FFPE tumor and matched blood samples of 989 Chinese patients with confirmed histology subtype of adenocarcinoma, consisting of 503 males and 486 females with a median age of 60 years, were collected for NGS-based 450 cancer genes panel assay. Genomic alterations including single nucleotide variations (SNV), short and long insertions/deletions (Indel), copy number variations (CNV) and gene rearrangements in selected genes were assessed. About 57% of Chinese lung adenocarcinoma patients harbored at least one EGFR genomic alteration, which was mainly composed of patient with SNVs and Indels (74%), both gene amplifications and SNVs/Indels (23%), gene amplifications only (2.7%) and gene rearrangements (0.5%). 20% of the patients with SNVs and Indels in EGFR carried more than one EGFR mutations. Moreover, EGFR gene rearrangement was mutually exclusive with other types of genomic alterations. Exon 19 deletions and L858R substitution were the most common EGFR mutations, which accounted for 37.9% and 33.7% of all EGFR alterations, respectively. Exon 20 insertions, the mostly insensitive variant to EGFR-TKIs, amounted to 3.7%, and the most common resistant alteration T790M accounted for 5.9%. Uncommon EGFR mutations including L861Q, G719X, S768I and others were identified in 18.9% of patients with EGFR mutations. Further analysis of co-occurring EGFR mutations and kinase receptor fusions revealed that 1.1% (6 of 559) of EGFR mutated Chinese NSCLC patients harbored both EGFR mutations and known druggable kinase receptor fusions including ROS1, RET and NTRK. Three of the six patients received EGFR-TKI as the standard treatment. One patient achieved partial response for 10 months and two achieved stable disease for 5 and 4 months, respectively. About 38% of Chinese lung adenocarcinoma patients harbored more than one EGFR genomic alterations, and 19% of EGFR mutations identified in Chinese lung adenocarcinoma patients were uncommon mutations. In addition, 1.1% of EGFR mutated patients also harbored known druggable kinase receptor fusions. Though our preliminary data showed that the co-existence of EGFR mutations and kinase receptor fusions might be associated with shorter response time to EGFR-TKIs, further large cohort study is needed to validate this finding.

The comprehensive genomic profiling (CGP) diagnosis initially designed for targeted therapy is finding its way in cancer therapy with immune checkpoint inhibitors. Besides the utility of identifying targets for precision therapy, CGP also measures the tumor mutational burden (TMB) and the microsatellite instability status (MSI), which both are associated with the response to PD-1 blockade immunotherapy.

Identifying genomic alterations of actionable driver genes in non-small cell lung cancer (NSCLC) such as EGFR, ALK, ROS1 has been used as important evidences for first line treatments. Patients with driver mutations received matched target drugs could have significantly longer progression free and overall survival. FFPE tumor samples of 498 Chinese NSCLC patients including 279 males (56%) and 219 females (44%) with a median age of 60 were collected for next-generation sequencing (NGS)-based multi genes panel assay. Genomic alterations including single base substitution, short and long insertions/deletions, copy number variations, and gene rearrangement and fusions in selected genes were assessed. Different histological subtypes of adenocarcinoma (417/498, 83.7%), squamous carcinoma (68/498, 13.7%), mixed carcinoma (6/498, 1.2%) and large cell carcinoma (7/498, 1.4%) were included in the Chinese NSCLC cohort. The top ranked genomic alterations in driver genes were EGFR (47.8%), KRAS (10.0%), ALK fusions (8.2%), PIK3CA (7.0%), HER2 (6.2 %), PTEN (3.6%), BRAF (2.6%), MET (3.6%), RET fusions (1.6%), and ROS1 fusions (0.8%), which counts up to 86.9% of the 498 patients with at least one driver mutation. In addition to common driver mutations, rare mutation types such as EGFR-KDD, EGFR-RAD51, AMOTL2-NTRK1 and KIF13A-RET were also detected by deep sequencing assay. Our study revealed the landscape of driver gene mutations in 498 Chinese NSCLC patients. Comparing to the largest public NSCLC cohort from Foundation Medicine, mostly Western populations (N=6823, PMID: 27151654), we identified similar frequencies of some driver genes, but more ALK fusions (8.2% vs 3.9%), EGFR mutations (47.8% vs 20.0%) as druggable target genes, and less KRAS mutations (10.0% vs 32.0%) consistent with reported results. Totally 78.7% of the Chinese patients harbored at least one mutation in the 8 core driver genes including EGFR, ALK, BRAF, ERBB2, MET, ROS1, RET, or KRAS (vs. 71% in the FMI cohort). Our findings demonstrated that genomic profiling of driver genes in NSCLC showed significant differences among racial or ethnic groups, which indicated different treatment options between Eastern and Western populations.

Background: To date, ctDNA has been exhibiting its unprecedented translational potential in cancer care. However, accurate identification of comprehensive genomic alternations is rigorously needed for its clinical utility. Methods: Three biologically relevant reference materials with allele frequencies expected at 0.1%, 1% and 5% were used to analytically evaluate the accuracy and reproducibility. Clinically, 43 ctDNA samples from lung, liver, colorectal, breast and gastric cancers were genomically profiled and compared to the known alternations in their matched solid tumors, in terms of single base substitution, insertions/deletions, copy number variations and rearrangement. Results: The analytical validation demonstrated unprecedented accuracy: near 100% specificity (99.6%, 99.9% and 100%) and 95.8%, 100% and 100% sensitivity for 3 reference materials, respectively. The actual detection limit was as low as 0.05%. The reproducibility was assessed as 0.998 (jaccard index) by sequencing 2 replicates of each reference. In clinical validation, compared to matched FFPE results, this ctDNA assay showed overall 99.9% specificity and 89% sensitivity, with > 90% sensitivity when only drug-gable hotspots were concerned. Eight events of gene rearrangements involving known targeted genes of ALK (n = 4), ROS1 (n = 3) and MET (n = 1) were detected from seven patients with 100% sensitivity and 100% specificity, confirmed either by IHC or panel sequencing (depth > 1,000X) over their matched FFPE biopsies. Due to its typically low abundance, CNV from ctDNA was detectable only for those highly amplified genes ( > =8 copies) with > =4 exons, demonstrating 72.2% sensitivity and 99.5% specificity. Conclusions: Stringent criteria for both analytical and clinical validations are required for clinical utility of ctDNA. Our ctDNA assay has demonstrated high accuracy and reliability in comprehensively genomic profiling of ctDNA, especially in regard to druggable targets, which assures its translational utility in optimizing and monitoring targeted therapies in cancer management. Legal entity responsible for the study: OrigiMed Inc Funding: OrigiMed Inc Disclosure: W. Liu, S. Mu, J. Yao, H. Chen, Z. Hu, J. Hu, G. Chirn, H. Kang, K. Wang, M. Yao: Employee of OrigiMed Inc.

Background: Docetaxel is widely used in China as second-line therapy for advanced NSCLC, with an objective response rate (ORR) of 5%–10% and median progression-free survival (PFS) and overall survival (OS) of ∼3 and ∼7.5 months, respectively. In KEYNOTE-010, treatment with the humanized anti–PD-1 monoclonal antibody pembrolizumab significantly improved OS as second-line or later therapy in patients with advanced NSCLC expressing PD-L1. KEYNOTE-033 is a randomized open-label study comparing the efficacy and safety of pembrolizumab monotherapy with standard-of-care docetaxel monotherapy in patients (majority from China) with previously treated PD-L1–positive NSCLC. Trial design: Eligible patients in this phase 3 study are aged ≥18 years with confirmed stage III/IV or recurrent PD-L1–positive (tumor proportion score [TPS] ≥1%) NSCLC, with disease progression after ≥1 line of platinum-containing doublet therapy. Patients with tumors with EGFR-sensitizing mutations are excluded and those with ALK translocations must have disease progression on both platinum-containing doublet and ALK-directed tyrosine kinase inhibitor therapy. ∼740 eligible patients will be randomized 1:1 to receive pembrolizumab 2 mg/kg Q3W or docetaxel 75 mg/m2 Q3W. Treatment will be administered for 2 years/35 cycles (whichever is later), or until disease progression, intolerable toxicity, or withdrawal of consent. Randomization will be stratified by PD-L1 TPS (≥50% vs < 50%). Tumor response will be evaluated Q9W by RECIST v1.1 by blinded independent central review. Adverse events occurring during the study will be graded using NCI CTCAE v4.0. Primary endpoints are OS and PFS. Secondary endpoints include ORR and duration of response. Patient-reported outcomes are an exploratory objective. Enrollment has been initiated; 52 sites are planned including 25 in mainland China and others in Argentina, Philippines, Taiwan, Thailand, Mexico, Chile and Ukraine. Clinical trial indentification: ClinicalTrials.gov, NCT02864394. Legal entity responsible for the study: This research was supported by Merck & Co., Inc., Kenilworth, NJ, USA Funding: This research was supported by Merck & Co., Inc., Kenilworth, NJ, USA Disclosure: C. Zhou: Lecture honoraria: Eli Lilly, AstraZeneca, Boehringer Ingelheim, Roche, Sanofi Research Funding: Pfizer, Boehringer Ingelheim, C. Caglevic: Speaker: BMS, MSD, Boehringer Ingelheim, Tecnofarma Advisory and Consulting: BMS, MSD, Boehringer Ingelheim, Eli Lilly, AstraZeneca, Bayer Investigator: MSD, BMS, Boehringer Ingelheim, Bayer, Roche, Astra Zeneca, Astellas, Advaxis Acommodation Grants: Boehringer Ingelheim, J. Ge, Y. Zhou: Employment: MSD China, Shanghai, CN, B. Piperdi: Employment: Merck & Co., Inc., Kenilworth, NJ, US All other authors have declared no conflicts of interest.

Background: Gene fusion is typical structural variations (SV) in most cancers, which leads to constitutive activation of driver genes. Kinase fusions of ALK, ROS1 and RET are well recognized in non-small cell lung cancer (NSCLC), and patients with the kinase fusions could benefit from targeted therapies as first-line or routine treatments. Methods: FFPE tumor samples of 445 Chinese NSCLC patients were collected for next-generation sequencing (NGS) based panel assay, including 252 males (57%) and 193 females (43%) with a median age of 60. Genomic alterations including single base substitution, short and long insertions/deletions, copy number variations, and gene rearrangement in selected genes were assessed. Results: 55 out of 445 NSCLC patients (12%) harbored at least one gene rearrangement in ALK, ROS1, RET, EGFR, BRAF, NTRK1 or MET, including 26 males and 29 females (median age: 56). ALK fusion is the most frequent event detected in 7.6% of the pts. The frequency of RET and ROS1 fusions was 1.8% (8/446) and 0.9% (4/446) respectively. Six pts had rearrangements in EGFR (1.3%). MET, BRAF, and NTRK1 fusion was detected each in one pt (0.2%). Interestingly, several novel partner genes were identified in 9 pts (16%, 9/55), for instance, AMOTL2-NTRK1, KIF13A-RET, and ZC3H7A-BRAF. In addition, two ALK fusions were detected in a poorly differentiated lung adenocarcinoma (EML4-ALK and CDK15-ALK) with the distinct breakpoints. Conclusions: Our study described the landscape of gene fusions in 445 Chinese NSCLC patients. NGS technology showed the advantage to detect novel fusions and also provide structure information of partner genes which could potentially provide more precise treatment options. Legal entity responsible for the study: Origimed, Inc, Shanghai, China Funding: Origimed, Inc, Shanghai, China Disclosure: H. Chen, G.W. Chirn, K. Wang and M. Yao are employees of Origimed Inc. The other authors claim no conflicting interests.

EGFR mutations in plasma circulating free tumor-derived DNA (ctDNA) as a predictor of EGFR TKI efficacy in patients with NSCLC requires validation in prospective studies. The large, prospective Phase II, single-arm, multicenter BENEFIT study (CTONG1405; NCT02282267) validated the efficacy of first-line gefitinib in EGFR mutation-positive NSCLC detected in plasma ctDNA using droplet digital PCR (ddPCR).