Author: Rashmi Acharya, MS, Science and Research Specialist, GO2 for Lung Cancer

The 2021 World Conference on Lung Cancer (WCLC) had multiple researchers presenting their findings on broad areas of research in early-stage lung cancer. These presentations bring highly encouraging news to the lung cancer community—an interest in understanding and establishing diagnostic and treatment methods for early stages, when the disease is more treatable. Some of these impactful presentations from WCLC are outlined below.

Adjuvant and Neo-Adjuvant Immunotherapy for Improved Survival

The IMPOWER 010 phase 3 trial tested how prior therapy affected the disease-free survival rate of Tecentriq (atezolizumab) as adjuvant (post-surgery) therapy compared to best supportive care in patients with early-stage non-small cell lung cancer (NSCLC). The results of the trial were overwhelmingly positive showing that Tecentriq is more effective than basic supportive care across most stages, and across most surgery types and prior chemotherapy regimens. Based on this data, Tecentriq was approved by the FDA as an adjuvant therapy (given after surgery) on October 15, 2021 for stage II-IIIA non-small cell lung cancer (NSCLC) that has PD-L1 levels greater than 1%. The trial did not separate the patients based on their type of lung cancer so further studies are needed to understand the effectiveness of the treatment on specific types, but this trial is a great first step in that direction.

Results from a separate phase 1 trial of Keytruda (pembrolizumab) given before surgery to early-stage patients were presented. The trial tested the safety and response rate of Keytruda in this patient group and recommended a phase 2 dose of the drug for further study. Early-stage lung cancer may benefit more from immunotherapy treatment in the neo-adjuvant (pre-surgery) setting. The results of the study showed that Keytruda is safe for use with a low 8% rate of serious side effects. 27% of patients in the study had a good response to the drug as a pre-surgery treatment, and a greater than 5 weeks’ time interval from treatment initiation to surgery resulted in higher rate of response. More and more trials are testing the application of different treatments in early-stage lung cancer, pushing the treatments available for early-stage further.

Application of Liquid Biopsy in Early-Stage Lung Cancer

Researchers presented their studies on use of micro-RNA (a type of RNA that controls the kinds and amounts of proteins cells make) for diagnostic purposes and circulatory tumor DNA (ctDNA) for monitoring residual diseases and early recurrence. Based on a previously published study that created a diagnostic model using microRNA (miRNA), students at Del Mar High school presented an updated miRNA diagnostic model for early-stage lung cancer. They tested and validated the model in 1566 lung cancer patients and 2178 controls. The results of their study suggest that the updated model had a higher accuracy than the original model. The test could potentially be used to develop miRNA-based diagnostic and recurrence monitoring tests.

Similarly, another study looked at ctDNA as a marker for patients with high or low risk of recurrence. Positive ctDNA test results at pre-surgery and continuous tests after surgery were associated with recurrence in early-stage lung cancer. The lead time in their study between ctDNA detection and detection through radiology was 3.9 months meaning the recurrence could potentially be detected 4 months earlier if the test holds true in further studies. The research team hopes to further develop this test to be able to detect recurrence by liquid biopsy before it can be detected through radiology.

Outcomes of Radiation Treatment

Radiation is a commonly used treatment in early-stage cancers usually combined with surgery or chemotherapy. There were a few studies on outcomes of radiation treatment. Two studies focused on stereotactic body radiation therapy (SBRT) testing impact of the treatment on local recurrence. One study showed that SBRT is safe for use in local recurrence. However, repeat SBRT had worse local control and no difference in distant metastasis-free survival. The results do not support repeat treatment with SBRT at the same location. The second study on radiation showed that local control does have an impact on overall survival and the treatment while effective could further be optimized to bring more benefit to patients. Clinical trials in this area are ongoing.

The Impact of Driver Mutations on Recurrence and Survival

Previous studies suggest that specific tissue subtypes in EGFR mutant cancers (solid or micropapillary) are a risk factor for recurrence. Results were presented on a study about the impact of EGFR mutations and presence of high-risk subtype in predicting recurrence in stage I lung adenocarcinoma. Out of 721 patients enrolled in the study, 375 had an EGFR mutation and 346 did not have an EGFR mutation. In the EGFR mutant group, the presence of high-grade subtypes negatively impacted outcomes. The EGFR group with high-risk subtype had lower 5-year recurrence-free survival rates. There was no significant difference in overall survival. The definition of “high risk of recurrence” among subtype still is not clear and more research is needed to understand the interaction between EGFR mutation status and specific tissue subtypes. Presence of a high-risk subtype could be used as a potential predictor of recurrence in EGFR mutant cancers.

Adjuvant chemotherapy was tested in stage I EGFR mutation as adjuvant chemotherapy. Adjuvant chemotherapy has previously shown survival benefit in stage I patients without EGFR mutations, but its effects have not been studied in early-stage EGFR mutant cancers. Adjuvant chemotherapy did not show survival benefit in EGFR mutant group. In patients without an EGFR mutation, the recurrence-free survival and overall survival rates were significantly better.

Immune Profiles to Predict Risk of Recurrence

Multiple studies are ongoing to understand the characteristics of tumor tissues, tumor adjacent tissue, and tumor adjacent lymph nodes to isolate any indicators of cancer recurrence. An early phase study showed potential mutation and amplification in tumor and tumor adjacent tissues that might predict recurrence, and the research team identified defective immune function of dendritic cells (a type of immune cell) in recurrent tumors. Furthermore, analysis of resected lymph nodes highlighted that density of lymph nodes and CD4 expression in lymph nodes are associated with survival. As this is early phase research, no specific predictors are established but further avenues are developing to better understand risks of recurrence.

Treatment Patterns in Early- Stage ALK-positive Lung Cancer

In advanced settings, ALK targeted therapies have transformed lung cancer treatment, however, ALK testing for early-stage NSCLC is not standard of care yet. At Princess Margaret Cancer Center in Toronto, biomarker testing is carried out in patients of all stages and researchers were able to present results of a study of 45 early-stage ALK-positive patients that had received different types of treatments. Most stage I-II patients were treated with surgery and adjuvant chemotherapy and most stage III patients had chemotherapy and radiation combination treatment. The median progression free survival (PFS) of the patients in the study was 27.6 months and it differed significantly based on stage at initial diagnosis, with stage I patients having the longest interval between diagnosis and recurrence. A portion of stage III patients received Imfinzi (durvalumab) after their chemoradiation treatment. Evaluation of the Imfinzi group did not show significant benefit and in fact, showed a similar progression-free survival period as chemoradiation treatment. Out of the total 45 patients, 30 had cancer recurrence and most received an ALK TKI as first treatment after relapse. The group that had received Imfinzi prior to an ALK TKI did not have any major side effects after receiving TKI.