Detection of Circulating Tumor DNA After Stereotactic Ablative Radiotherapy in Patients With Unbiopsied Lung Tumors (SABR-DETECT).

For patients with stage I/IIA non-small-cell lung cancer (NSCLC), surgical resection is the standard treatment. However, some of these patients are not candidates for surgery or refuse a surgical option. Definitive stereotactic ablative radiotherapy (SABR) is a standard approach in these patients. Approximately 15% of patients undergoing SABR for localized NSCLC will experience a recurrence within 2 years. Furthermore, many of these patients are deemed appropriate for SABR without a tissue diagnosis, based on the likelihood of malignancy which can be calculated by validated models. A liquid biopsy, detecting ctDNA, would be useful in early detection of recurrences, and documenting a cancer diagnosis in patients without a biopsy. This is a multi-institutional study enrolling patients with suspected stage I/IIA NSCLC and a pretreatment likelihood of malignancy of ≥60% using the validated models for patients without a tissue diagnosis, in cohort 1 (n = 45). The second cohort will consist of biopsied patients (n = 30-60). SABR will be delivered as per risk-adapted protocol. Plasma will be collected for ctDNA analysis prior to the first fraction of SABR, 24 to 72 hours after first fraction, and at 3, 6, 9, 12, 18, and 24-months. The patients will be followed up with imaging at 3, 6, 9, 12, 18, and 24-months. The primary objective is to assess whether a cancer detection liquid biopsy platform can predict recurrence of NSCLC. The secondary objectives are to assess the impact of SABR on detection rates of ctDNA in patients undergoing SABR and to correlate ctDNA positivity and pretreatment probability of malignancy (NCT05921474).

Radiation and immune checkpoint inhibitors in the treatment of oligometastatic non-small-cell lung cancer: a practical review of rationale, recent data, and research questions.

The combined use of stereotactic ablative radiotherapy (SABR) and immune checkpoint inhibitors (ICIs) is an emerging treatment paradigm for oligometastatic non-small-cell lung cancer (NSCLC). Recent phase I and II trial data suggest that SABR to multiple metastases in addition to ICI use is safe and effective with promising progression-free survival and overall survival signals. There is great interest in capitalizing on combined immunomodulation from these two modalities for the treatment of oligometastatic NSCLC. Ongoing trials seek to validate the safety, efficacy, and preferred sequencing of SABR and ICI. This narrative review of the role of SABR when combined with ICI in oligometastatic NSCLC discusses the rationale for this bimodality treatment, summarizes recent clinical trial evidence, and proposes key principles of management based on the available evidence.

Exploitation of treatment induced tumor lysis to enhance the sensitivity of ctDNA analysis: A first-in-human pilot study.

INTRODUCTION: Blood-based liquid biopsies examining circulating tumour DNA (ctDNA) have increasing applications in non-small cell lung cancer (NSCLC). Limitations in sensitivity remain a barrier to ctDNA replacing tissue-based testing. We hypothesized that testing immediately after starting treatment would yield an increased abundance of ctDNA in plasma because of tumor lysis, allowing for the detection of genetic alterations that were occult in baseline testing. METHODS: Three prospective cohorts of patients with stage III/IV NSCLC were enrolled. Cohort 1 (C1) contained patients starting platinum doublet chemoradiation (n = 10) and cohort 2 (C2) initiating platinum doublet cytotoxic chemotherapy ± immunotherapy (n = 10). Cohort 3 (C3) contained patients receiving palliative radiation. Two baseline samples were collected. In C1 and C2, subsequent samples were collected 3, 6, 24 and 48 h post initiation of chemotherapy. Patients in C3 had samples collected immediately prior to the next three radiotherapy fractions. Samples were analyzed for ctDNA using the 36-gene amplicon-based NGS Inivata InVisionFirst®-Lung assay. RESULTS: A total of 40 patients were enrolled. Detectable ctDNA was present at baseline in 32 patients (80%), 4 additional patients (50%) had detectable ctDNA in post-treatment samples. Seven patients with detectable ctDNA at baseline (23%) had new genetic alterations detected in post-treatment samples. Mutant molecule numbers increased with treatment in 24 of 31 (77%) pts with detectable ctDNA. ctDNA levels peaked a median of 7 h (IQR:2-26 h) after the initiation of chemotherapy and a median of 2 days (IQR:1-3 days) after radiation was commenced. CONCLUSION: ctDNA levels increase in the hours to days after starting treatment. ctDNA testing in the acute post-treatment phase can yield results that were not evident in pre-treatment testing. Application of this principle could improve ctDNA utility as an alternate to tissue-based testing and improve sensitivity for the detection of treatment-resistant clones.(NCT03986463).

The Influence of Adjuvant Chemotherapy Dose Intensity on Five-Year Outcomes in Resected Colon Cancer: A Single Centre Retrospective Analysis.

There is evidence that achieving a dose intensity > 80% in adjuvant colon cancer treatment improves survival. In total, 192 consecutive patients with resected stage III and high-risk stage II colon cancer that received adjuvant chemotherapy were retrospectively analyzed. Patients who received at least 6 weeks of adjuvant therapy were included. The primary objective was to assess the influence of dose index (DI) and relative dose intensity (RDI) on DFS and OS at 3 and 5 years in patients receiving fluorouracil-based doublet therapy with oxaliplatin (FOLFOX) (5-FU and oxaliplatin assessed separately), or capecitabine monotherapy. In the capecitabine group, DFS rates for 3 and 5 years were 66.7% and 57.6%, respectively, while OS rates were 80.3% and 66.7%, respectively. Those who received FOLFOX had DFS rates of 76.9% and 71.2% at 3 and 5 years, respectively. OS rates were 86.4% and 76.7% at 3 and 5 years, respectively. Median RDI was 73.8% for capecitabine and 76.3% and 85.6% for the oxaliplatin and 5-FU components respectively. Based on a multivariate analysis in patients receiving FOLFOX, those with an oxaliplatin DI > 80% had improvements in DFS and OS compared to those with an oxaliplatin DI of ≤80%. Otherwise, there was no significant difference in DFS or OS when comparing patients who achieved an RDI or a DI of above versus below 80% in the patients receiving adjuvant chemotherapy for resected colon cancer.