Dr Pellini on the Clinical Utility of ctDNA Assays in NSCLC

Bruna Pellini, MD, assistant member, Department of Thoracic Oncology, Moffitt Cancer Center; assistant professor, Morsani College of Medicine, University of South Florida, discusses the potential utility of circulating tumor DNA (ctDNA) assays in clinical practice for non–small cell lung cancer, as well as highlights the need for ongoing research to make this a more accurate, sensitive, and potentially predictive tool for treatment selection.

Pellini begins by noting that ctDNA is a promising prognostic biomarker in oncology. Although ctDNA holds potential for guiding treatment decisions and risk stratification, concerns persist regarding the reliability and clinical utility of current assays due to limitations in assay sensitivity and suitability for longitudinal monitoring, Pellini states, explaining that ctDNA is not ready for use in clinical practice.

Current assays lack the necessary sensitivity to reliably detect minimal residual disease (MRD), Pellini says. False negatives are prevalent in current ctDNA assays, compromising their effectiveness in guiding treatment decisions and longitudinal monitoring, she explains.

Due to these limitations, Pellini opts not to integrate ctDNA testing into her clinical decision-making process. She highlights the need for improved assay technologies to enhance ctDNA sensitivity and accuracy, acknowledging ongoing developments in this area. Testing for ctDNA may be useful for indicating a high risk of disease recurrence in patients, but it may be less useful in guiding adjuvant immunotherapy decisions following chemoimmunotherapy and surgery.

Although many are eager to integrate ctDNA testing into clinical practice, others are hesitant due to the risk of false negatives, Pellini notes. She emphasizes that the current technology does not meet the necessary standards for making treatment decisions, particularly in assessing MRD and predicting disease outcomes accurately. 

Ultimately, it is vital to develop enhanced treatment strategies in the adjuvant setting for patients with micro-metastatic disease detected by ctDNA, Pellini adds. Further research and technological advancements are needed to enhance the sensitivity and accuracy of ctDNA assays to realize their full potential as valuable tools in cancer management, Pellini concludes.

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Bruna Pellini, MD, discusses the utility of circulating tumor DNA assays in non–small cell lung cancer.

Dr Pellini on the Development of Increasingly Sensitive ctDNA Assays in NSCLC

Bruna Pellini, MD, assistant member, Department of Thoracic Oncology, Moffitt Cancer Center; assistant professor, Morsani College of Medicine, University of South Florida, discusses how blood-based lung cancer assays have evolved over time and the importance of developing circulating tumor DNA assays with increased sensitivity to accurately determine optimal treatments for patients with non–small cell lung cancer.

Many oncologists are now opting for neoadjuvant chemoimmunotherapy following a paradigm shift in the management of early-stage NSCLC, Pellini begins. Neoadjuvant approaches have substantially increased patient response rates; however, their success has made obtaining surgical specimens for analysis more challenging, she states. Approximately 30% to 40% of these patients will achieve a major pathological response (MPR) or complete pathological response (pCR) with neoadjuvant therapy, leaving limited tissue available for further testing, Pellini expands.

Traditional tissue-based assays developed in the past require a substantial amount of cancer cells and are tumor-informed, meaning they rely on specific tumor characteristics for analysis, Pellini explains. Although these assays demonstrate good sensitivity in detecting disease recurrence, the absence of sufficient surgical specimens from patients with NSCLC poses a significant challenge in their application, she says.

Development of tumor-agnostic, tumor-uninformed assays that are entirely blood-based may help address this challenge, Pellini states. However, current blood-based assay technologies face limitations in sensitivity, Pellini notes. This leads to concerns about accurately detecting minimal residual disease (MRD) and disease recurrence solely from blood samples, Pellini adds.

Effective assays must address the limitations of current technologies to provide reliable prognostic information and guide treatment decisions in early-stage NSCLC, Pellini says, emphasizing that liquid biopsy assays need to be developed with increased sensitivity to detect disease recurrence in the form of MRD. In doing so, oncologists can more accurately identify patients with MRD-negative disease and tailor treatment strategies accordingly, she concludes.

Bruna Pellini, MD, discusses the importance of developing circulating tumor DNA assays with increased sensitivity. 

Bruna Pellini, MD, assistant member, the Department of Thoracic Oncology, H. Lee Moffitt Cancer Center, assistant professor, Morsani College of Medicine, the University of South Florida, discusses the use of circulating tumor DNA (ctDNA) monitoring to inform maintenance outcomes in patients with advanced non–small cell lung cancer (NSCLC) treated with induction therapy with atezolizumab (Tecentriq), carboplatin, and nab-paclitaxel (Abraxane).

Pellini and colleagues presented data from a retrospective study that examined ctDNA in patients treated with the induction regimen, and they concluded that this monitoring could inform durability of treatment benefit and help identify patients at a high risk for disease progression to allow for selection of personalized maintenance strategies.

Findings from this investigation could be important for consideration in clinical trial designs in the future, Pellini begins, noting that ctDNA represents a feasible biomarker that can be studied at different time points. Future studies should examine personalized maintenance therapies, according to the risk of the patient, she explains. Among ctDNA-positive patients, the overall response rate was 43%, and these patients could be considered high risk for progression, she continues. The study also found that additional cycles of therapy was not associated with improved outcomes in patients who were ctDNA positive on day 1 of cycle 4. Therefore, it important to develop strategies for these patients, since treatment with the same therapy did not elicit an improvement, Pellini says.

The goal of the study was to attempt to show that there is a role for ctDNA monitoring in NSCLC; however, having a biomarker that only informs an investigator about a patient’s risk is not enough, Pellini continues. Therefore, creating trials that take examine different, personalized approaches could help improve outcomes for high-risk patients, Pellini concludes.

Bruna Pellini, MD, discusses the use of circulating tumor DNA monitoring to inform maintenance outcomes in patients with advanced non–small cell lung cancer treated with induction therapy with atezolizumab, carboplatin, and nab-paclitaxel. 


Dr Pellini on the Use of ctDNA Monitoring After Chemoimmunotherapy Induction in NSCLC

Bruna Pellini, MD, assistant member, Department of Thoracic Oncology, H. Lee Moffitt Cancer Center, assistant professor, Morsani College of Medicine, University of South Florida, discusses the challenges of using topotecan as a comparator arm for second-line clinical trials in extensive-stage small cell lung cancer (ES-SCLC). 

A majority of clinical trials evaluating therapies for the second-line treatment of patients with ES-SCLC utilize topotecan as the comparator arm, says Pellini. However, topotecan is rarely given to patients in practice, Pellini explains.

Lurbinectedin (Zepzelca) is a well-tolerated transcription factor inhibitor that was approved in June 2020 by the FDA for the treatment of patients with metastatic SCLC who have disease progression after platinum-based chemotherapy. The agent is administered every 3 weeks, whereas topotecan is administered on days 1 through 5 of 21-day cycles, Pellini says. Additionally, topotecan is associated with more toxicity compared with lurbinectedin, Pellini says.

Although lurbinectedin is a relatively new agent in the SCLC armamentarium, the agent could offer another option for comparison against investigational agents in clinical trials, Pellini says. Other chemotherapy options are available in the second-line setting for this patient population; however, these agents are also associated with significant toxicity, Pellini says. Ultimately, lurbinectedin could offer patients a well-tolerated and easy-to-administer regimen following platinum-based doublet therapy, concludes Pellini. 

Bruna Pellini, MD, discusses the challenges of using topotecan as a comparator arm for second-line clinical trials in extensive-stage small cell lung cancer.   



Bruna Pellini, MD

Articles

Dr Pellini on the Clinical Utility of ctDNA Assays in NSCLC

Dr Pellini on the Development of Increasingly Sensitive ctDNA Assays in NSCLC

Dr Pellini on the Use of ctDNA Monitoring After Chemoimmunotherapy Induction in NSCLC

Dr. Pellini on the Challenges of Using Topotecan as a Comparator Arm in Recurrent ES-SCLC