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The noninvasive blood-based targeted methylation assay ELSA-seq identified early cancers with high specificity and provided accurate predictions of the tissue of origin, according to findings from the THUNDER-II study presented during the 

At 99.5% training specificity (95% CI, 96.7%-100%), the cross-validated sensitivity of the assay was 79.9% (95% CI, 74.6%-84.4%). The results proved to be consistent in the validation set, with 98.3% specificity (95% CI, 95.8%-99.4%) and 80.6% sensitivity (95% CI, 76.0%-84.4%) reported across stages and cancer types.

“In general, the performance was consistent in the training and validation set,” Qiang Gao, MD, lead study author and professor in the Department of Liver Surgery and Transplantation, Liver Cancer Institute and Zhongshan Hospital, Fudan University, said during a virtual presentation of the data. “Taken collectively, these findings highlight the potential implementation of ELSA-seq as a noninvasive multicancer detection test.”

Early cancer detection can provide clinical benefits, particularly for those with inadequate screening methods.

ELSA-seq is a sensitive targeted methylation sequencing assay that interrogates epigenetic alterations from circulating cell-free DNA (cfDNA), enabling simultaneous identification and localization of multiple cancer types. The target panel covers 80,672 CpG sites, spanning genomic regions of approximately 1.05 Mb. A total of 8312 co-methylation blocks served as markers to create the classification model.

The THUNDER (THe UNintrusive Detection of Early-stage cancer) program was comprised of 2 phases: THUNDER-I (n = 896) and THUNDER-II (n ~2500). THUNDER-II is a substudy of THUNDER, which is a pilot study designed for the development and validation of ELSA-seq in 6 tumor types: lung, colorectal, liver, ovary, pancreas, and esophagus; these types account for approximately 52% of all cancer cases in China.

The first phase of the research was designed to evaluate the performance of ELSA-seq in high and low concentrations of ctDNA, according to Gao.

Previously reported findings from the THUNDER-I study, which were presented during the 2020 AACR Special Conference on Advances in Liquid Biopsies meeting, demonstratedwith an overall specificity of 95% (n = 215), detection rates of 65% (n = 86), 82% (n = 125), 88% (n = 101), and 94% (n = 84) for stage I to IV solid tumors, respectively.

 The assay also accurately predicted the tissue of origin in 93% (n = 117) of cases in the validation set.

In a substudy, ELSA-seq identified approximately double the number of patients (n = 27) as deep mutation sequencing (n = 15), with no false positives. Moreover, the assay did not require any biopsied tissue to detect ctDNA at an allele frequency as low as 0.02%.

THUNDER-II consisted of 5 steps: marker discovery (n = 247), panel validation (n = 599), model training (n = 469), validation (n = 639), and the blind test, which is ongoing.

In the marker discovery phase of the research, 247 individuals underwent tissue testing (n = 116 patients with cancer; n = 131 non-cancer controls) alongside 5374 individuals from The Cancer Genome Atlas and Gene Expression Omnibus Database (n = 4366 patients with cancer; n = 1008 non-cancer controls).

In the panel validation phase, 599 individuals underwent tissue and blood testing (n = 249 patients with cancer; n = 350 non-cancer controls).

In the final assay validation phase, patients underwent blood testing in 1 of 3 groups: the training set (n = 274 patients with cancer; n = 195 non-cancer controls), the validation set (n = 351 patients with cancer; n = 288 non-cancer controls), and an independent validation set, which is ongoing.

Baseline characteristics indicated that patients with cancer and non-cancer controls had comparable age, gender, and smoking status in the training and validation sets. Moreover, patients with different stages and cancer types were well represented in the cancer group in the training and validation sets, and 80.0% patients were diagnosed at early stages (stage I to III).

Among non-cancer controls in the training set (n = 195), the mean age was 53 (range, 40-72) and the majority were female (n = 128; 70%). Among patients with cancer (n = 274), the mean age was 60 (range, 47-74), the minority were female (n = 110; 40%), and the clinical stage distribution was as follows: stage I (n = 73; 27%), stage II (n = 63; 23%), stage III (n = 97; 35%), and stage IV (n = 41; 15%). The training set included 50 patients with lung cancer, 46 patients with colorectal cancer (CRC), 48 patients with liver cancer, 50 patients with ovarian cancer, 40 patients with pancreatic cancer, and 40 patients with esophagus cancer.

Among non-cancer controls in the validation set (n = 288), the mean age was 54 (range, 40-74) and the majority were female (n = 171; 59%). Among patients with cancer (n = 351), the mean age was 59 (range, 40-75), the minority were female (n = 22; 36%), and the clinical stage distribution was as follows: stage I (n = 83; 23%), stage II (n = 87; 25%), stage III (n = 94; 27%), and stage IV (n = 87; 25%). The validation set included 61 patients with lung cancer, 57 patients with CRC, 57 patients with liver cancer, 53 patients with ovarian cancer, 59 patients with pancreatic cancer, and 64 patients with esophagus cancer.

Additional findings demonstrated that, with regard to the localization of diseased organs, the classifier returned a tissue-of-origin result in 98.6% cases (n = 129). For single organ determinations, the predictive accuracy of the assay was 79% in the training phase and 82% in the validation phase. In the training phase, the predictive accuracy was highest for ovarian cancer (n = 34; 97%), followed by liver cancer (n = 39; 95%), 85% (n = 33; 85%), esophagus cancer (n = 21; 72%), lung cancer (n = 26; 65%), and pancreatic cancer (n = 21; 60%).

In the validation phase, the predictive accuracy was highest for liver cancer (n = 46; 100%), followed by ovarian cancer (n = 36; 97%), CRC (n = 34; 81%), esophagus cancer (n = 39; 80%), pancreatic cancer (n = 41; 72%), and lung cancer (n = 31; 69%).

For the top 2 organ determinations, the predictive accuracy was 89% and 87%, respectively.

“ELSA-seq also enabled accurate prediction of diseased organs, offering guidance for subsequent diagnostic steps,” said Gao.

Similar evaluation of a cfDNA methylation-based model in early cancer detection is underway in the prospective, multicenter, longitudinal PREDICT (Pan-canceR Early Detection projeCT) study.

 The study will enroll approximately 14000 participants. The development and validation of the model will be evaluated in patients with early-stage cancers or benign diseases, along with non-tumor (healthy) individuals in a 2-stage process. The sensitivity and specificity of the model in early cancer detection and the accuracy of the identification of the tissue of origin will be evaluated.

Gao Q, Li B, Cai S, et al. Early detection and localization of multiple cancers using a blood-based methylation assay (ELSA-seq). Presented at: 2020 ESMO Congress; November 20-22, 2020; Virtual. Abstract LBA3.

Li B, Xu J, Wang C, et al. Multiplatform analysis of early-stage cancer signatures in blood. Presented at: AACR Special Conference on Advances in Liquid Biopsies; January 13-January 16, 2020. Abstract 62552825.

Pan-canceR Early Detection projeCT (PREDICT). ClinicalTrials.gov. Updaeted July 22, 2020. Accessed November 20, 2020. 

https://clinicaltrials.gov/ct2/show/NCT04383353

The noninvasive blood-based targeted methylation assay ELSA-seq identified early cancers with high specificity and provided accurate predictions of the tissue of origin.

Blood-Based Methylation Assay Enables Early, Accurate Detection of Solid Tumors 

Patients with extensive-stage small-cell lung cancer (ES-SCLC) who were treated with durvalumab (Imfinzi) plus platinum-based chemotherapy (EP) in the CASPIAN trial derived a long-term benefit 3 times greater than those treated with chemotherapy alone. However, exploratory subgroup analysis of patients who derived a progression-free survival (PFS) benefit lasting longer than 12 months did not reveal any clinical characteristics that could serve as predictive factors for benefit with the monoclonal antibody.

Further, tumor mutational burden, evaluable in 35% of the intention-to-treat population, was not predictive of an improvement in overall survival (OS) for patients.

“Patients in all treatment arms with PFS greater than 12 months had improved outcomes including exceptional long-term benefit observed with OS rates greater than 75%,” Ju Ho Ji, MD

, said in a presentation of the data during the ESMO Asia Congress 2020. “There were no unique clinical characteristics that appear to identify patients who derive long-term benefit.” 

Ji is a professor in the Division of Hematology and Oncology at Samsung Changwon Hospital and a professor of medicine at the Sungkyunkwan University School of Medicine in Korea.

Patients with treatment-naïve ES-SCLC enrolled in the phase 3 CASPIAN trial (NCT03043872) received either durvalumab plus tremelimumab with EP (n = 268), durvalumab plus EP (n = 268), or EP alone (n = 269). The addition of the CTLA-4 monoclonal antibody tremelimumab to the combination of durvalumab and EP did not significantly improve outcomes for patients.

In data presented at the 2020 ASCO Virtual Scientific Program, durvalumab plus EP demonstrated sustained improvement in OS at 2-year follow-up compared with EP alone. The median OS was 12.9 months versus 10.5 months, respectively (HR, 0.75; 95% CI, 0.62-0.91; 

 = .0032).2 The survival rate at 2 years was 22% in the experimental arm compared with 14% in the control arm. The PFS data was not formally tested for statistical significance, however the PFS rates at 2 years favored the combination (11.0% vs 2.9%, respectively).

Subgroup Analyses Demonstrate Sustained Response

PFS lasting at least 12 months was the preliminary threshold to identify potential prognostic factors. In total, 45 of 265 evaluable patients (17%) treated with durvalumab plus chemotherapy experienced a PFS lasting at least 12 months. In the EP alone arm, 12 of 266 evaluable patients (4.5%) met the threshold for analysis. In order to increase the sample size of the subgroup a third subset of patients composed of patients from both the durvalumab plus EP and durvalumab plus tremelimumab and EP arms (immunotherapy [IO] combined). Eighty-seven of 531 evaluable patients (16.4%) were included in the IO combined arm.

In all response arms for patients with a PFS lasting at least 12 months, investigators observed improved overall response rate (ORR) and duration of response (DOR). Specifically, the confirmed ORR for patients in the durvalumab plus EP arm was 96% and the median time to response was 43 days (range, 33-155). In the EP alone arm, the ORR for 12 patients was 100% with a median time to response of 42.5 days (range, 36-592). The median DOR for the combination was not reached (95% CI, 18–not estimable [NE]) compared with 20 months with EP alone (95% CI, 12–NE). Finally, at 24 months, 54% of patients remained in response in the durvalumab plus EP arm compared with 48% in the EP alone arm.

“Notably, there were some patients who had baseline brain or liver metastases who derived long-term benefit,” Li noted. Specifically, 7% and 20% of patients with brain and liver metastases, respectively, in the durvalumab plus EP arm experienced PFS lasting at least 12 months, compared with 0% and 17% in the EP alone arm.

In OS analysis for these subgroups, the median OS was not reached across arms and each arm demonstrated an OS benefit of greater than 75%. Specifically, the OS rates for the durvalumab plus EP arm, the IO combined arm, and the EP alone arm were 76.7%, 82.2%, and 83.3%, respectively. In those patients who had a PFS of less than 12 months, the OS rates were 11.1%, 11.0%, and 10.4%, respectively.

In terms of safety, the incidence of grade 3/4 adverse effects (AEs) was higher in the EP alone arm (75%) compared with the durvalumab plus EP (60%) and IO combined (67%) arms. Treatment-related AEs leading to death as assessed by investigators were observed in 2% of patients in the combination arm. No treatment-related AEs resulted in the death of patients in the EP alone arm.

Although the subgroup analysis did not reveal a prognostic factor for patients with ES-SCLC, Ji noted that further investigations are ongoing to stratify patients who may have a long-term benefit.

1. Ji JH, Goldman JW, Garassino MC, et al. Durvalumab (D) ± tremelimumab (T) + platinum-etoposide (EP) in 1L ES-SCLC: characterization of long-term clinical benefit and tumour mutational burden (TMB) in CASPIAN. Presented at: European Society for Clinical Oncology Asia Congress 2020; November 20-22, 2020; Virtual. Abstract 379MO.

2. Paz-Ares LG, Dvorkin M, Chen Y, et al. Durvalumab ± tremelimumab + platinum-etoposide in first-line extensive-stage SCLC (ES-SCLC): updated results from the phase III CASPIAN study. 

. 2020;38(suppl 15):9002. doi: 10.1200/JCO.2020.38.15_suppl.9002

November 20, 2020 - Exploratory subgroup analysis of patients with extensive-stage small-cell lung cancer who derived a progression-free survival benefit with durvalumab plus platinum-based chemotherapy lasting longer than 12 months in the CASPIAN trial did not reveal any clinical characteristics that could serve as predictive factors for benefit with the monoclonal antibody.

ESMO Asia Congress | Conference

Blood-Based Methylation Assay Enables Early, Accurate Detection of Solid Tumors

Prognostic Identifiers for ES-SCLC Are Not Revealed in CASPIAN Subgroup Analysis