Local Consolidative Therapy Research Articles

Circulating Tumor DNA-Guided De-Escalation Targeted Therapy for Advanced Non−Small Cell Lung Cancer

Uninterrupted targeted therapy until disease progression or intolerable toxic effects is currently the routine therapy for advanced non-small cell lung cancer (NSCLC) involving driver gene variations. However, drug resistance is inevitable. To assess the clinical feasibility of adaptive de-escalation tyrosine kinase inhibitor (TKI) treatment guided by circulating tumor DNA (ctDNA) for achieving complete remission after local consolidative therapy (LCT) in patients with advanced NSCLC. This prospective nonrandomized controlled trial was conducted at a single center from June 3, 2020, to July 19, 2022, and included 60 patients with advanced NSCLC with driver variations without radiologically detectable disease after TKI and LCT. The median (range) follow-up time was 19.2 (3.8-29.7) months. Data analysis was conducted from December 15, 2022, to May 10, 2023. Cessation of TKI treatment and follow-up every 3 months. Treatment was restarted in patients with progressive disease (defined by the Response Evaluation Criteria in Solid Tumors 1.1 criteria), detectable ctDNA, or elevated carcinoembryonic antigen (CEA) levels, whichever manifested first, and treatment ceased if all indicators were negative during follow-up surveillance. Progression-free survival (PFS). Secondary end points were objective response rate, time to next treatment, and overall survival. Among the total study sample of 60 participants (median [range] age, 55 [21-75] years; 33 [55%] were female), the median PFS was 18.4 (95% CI, 12.6-24.2) months and the median (range) total treatment break duration was 9.1 (1.5-28.1) months. Fourteen patients (group A) remained in TKI cessation with a median (range) treatment break duration of 20.3 (6.8-28.1) months; 31 patients (group B) received retreatment owing to detectable ctDNA and/or CEA and had a median PFS of 20.2 (95% CI, 12.9-27.4) months with a median (range) total treatment break duration of 8.8 (1.5-20.6) months; and 15 patients (group C) who underwent retreatment with TKIs due to progressive disease had a median PFS of 5.5 (95% CI, 1.5-7.2) months. For all participants, the TKI retreatment response rate was 96%, the median time to next treatment was 29.3 (95% CI, 25.3-35.2) months, and the data for overall survival were immature. The findings of this nonrandomized controlled trial suggest that this adaptive de-escalation TKI strategy for patients with NSCLC is feasible in those with no lesions after LCT and a negative ctDNA test result. This might provide a de-escalation treatment strategy guided by ctDNA for the subset of patients with advanced NSCLC. ClinicalTrials.gov Identifier: NCT03046316.

Oligo-residual disease in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer: incidence, pattern of failure, and clinical value of local consolidative therapy

ObjectivesTo investigate the feasibility and potential clinical value of local consolidative therapy (LCT) in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer (NSCLC).Materials and methodsPD-1/PD-L1 inhibitor-treated metastatic NSCLC patients with measurable disease in three academic centers were screened and those with adequate follow-up were included. Oligo-residual disease (ORD) was defined as residual tumors limited to three organs and five lesions evaluated at the best response among patients with partial response or stable disease after PD-1/PD-L1 inhibitors. Oligometastatic and multiple-metastatic disease (OMD/MMD) were similarly classified at baseline. Locoregional interventions, administered after effective treatment of PD-1/PD-L1 inhibitors and before initial disease progression, were defined as LCT. Patterns of initial progressive disease (PD) were classified as involving only residual sites (RP), only new sites (NP), or a combination of both (BP).ResultsAmong the 698 patients included, ORD was documented in 73 (47.1%) of 155 patients with baseline OMD and 60 (11.0%) of 543 patients with baseline MMD. With a median follow-up of 31.0 (range, 6.0–53.0) months, 108 patients with ORD developed initial PD, with RP, NP, and BP occurring in 51 (47%), 23 (21.3%), and 34 (31.5%), respectively. Among the 133 patients with ORD, those receiving LCT (n = 43) had longer progression-free survival (HR = 0.58, 95% CI 0.40–0.85, p = 0.01) and overall survival (HR = 0.49, 95% CI 0.30–0.79, p < 0.0001).ConclusionORD occurs with a clinically relevant frequency among PD-1/PD-L1 inhibitor-treated metastatic NSCLC patients and LCT may provide extra survival benefits in those with ORD.

NRG-LU002: Randomized phase II/III trial of maintenance systemic therapy versus local consolidative therapy (LCT) plus maintenance systemic therapy for limited metastatic non-small cell lung cancer (NSCLC).

8506 Background: First line therapy options for advanced NSCLC without actionable molecular alterations include immunotherapy (IO) -/+ chemotherapy or chemotherapy alone. NRG-LU002 was a randomized phase II/III study assessing the benefits of local consolidative therapy (LCT) when added to systemic therapy as maintenance in management of oligometastatic NSCLC. Methods: Eligible patients had metastatic NSCLC with 3 or fewer extracranial metastatic sites (excluding primary) exhibiting at least stable disease after 4 cycles of 1st line systemic therapy. Patients were randomized 1:2 to maintenance systemic therapy or LCT (radiation and/or surgery) followed by maintenance systemic therapy until progression, death, or intolerable toxicity. Stratification factors included histology and IO use. In the randomized phase II (RPhII) portion of the study, the primary endpoint was progression-free survival (PFS) with a planned decision analysis after 216 patients were enrolled and 138 PFS events observed. Secondary endpoints included overall survival (OS), quality of life, and toxicity. The RPhII portion was designed to provide at least 95% power to detect a PFS hazard ratio (HR) of 0.60 at 1-sided significance level of 0.15, and the phase III portion warranted only if the estimated HR was less than 0.83. Results: NRG-LU002 accrual was initiated in 4/2017 and suspended in 11/2021 when the RPhII portion sample size was met. Following the planned interim analysis, the study was closed in 12/2023. Overall, 215 patients (81 -LCT arm, 134 +LCT arm) were enrolled from 68 sites with a median age of 65 years (40-86), 77% white, 95% PS 0/1, 78% non-squamous histology, and 90% having received IO-based systemic therapy. Median follow-up among all/surviving patients were 21.9/29.4 months, respectively. With 138 PFS events from both arms, estimated 1-yr and 2-yr PFS rates were 48% (95% CI: 35.9, 59.0) and 36% (95% CI: 24.8, 47.2) in the maintenance systemic therapy arm and 52% (95% CI: 42.5, 59.8) and 40% (95% CI: 31.5, 48.6) in the LCT + maintenance systemic therapy arm, respectively (2-sided log-rank test p-value = 0.66). Corresponding HR was 0.93 (95% CI: 0.66, 1.31). Of 185 patients treated with IO-containing regimens, the PFS HR was 0.90 (95% CI: 0.61, 1.32). OS HR between two arms was 1.05 (0.70, 1.56) among all patients and 1.05 (0.68, 1.63) among IO-treated patients. For adverse events reported as definitely, probably or possibly related to treatment, there were more LCT + maintenance systemic therapy patients with overall grade 2 or higher toxicities (73% vs 84%) and grade 3 or higher pneumonitis (1% vs 10%). Conclusions: LCT added to IO-based 1st line systemic therapy was associated with a PFS HR of 0.90. Reducing toxicity and increasing biologically-driven patient selection may optimize this therapeutic ratio. Clinical trial information: NCT03137771 .

Lung resection after initial nonoperative treatment for non–small cell lung cancer

ObjectivesThe study objectives were to assess the outcomes of lung resection in patients with non–small cell lung cancer previously treated with nonoperative treatment and to identify prognostic factors associated with survival. MethodsPatients who underwent surgery (2010-2022) after initial nonoperative treatment at a single institution were identified from a prospectively maintained database. Exclusion criteria included metachronous cancer, planned neoadjuvant therapy, and surgery for diagnostic or palliative indications. Cox models were constructed for overall survival and event-free survival. Survival of patients with stage IV disease was compared with survival of a nonstudy cohort who did not undergo surgery. ResultsIn total, 120 patients met the inclusion criteria. Initial clinical stage was early stage in 16%, locoregionally advanced in 25%, and metastatic in 59% of patients. The indication for surgery was recurrence in 18%, local persistent disease in 23%, oligoprogression in 22%, and local control of oligometastatic disease in 38% of patients. Grade 3 or greater complications occurred in 5% of patients; 90-day mortality was 3%. Three-year event-free survival and overall survival were 39% and 73%, respectively. Male sex and lymphovascular invasion were associated with shorter event-free survival and overall survival; younger age and prior radiation therapy were associated with shorter overall survival. Patients with stage IV disease who received salvage lung resection had better overall survival than similar patients who received subsequent systemic therapy and no surgery. ConclusionsIn this selected, heterogeneous population, lung resection after initial nonoperative treatment for non–small cell lung cancer was safe. Surgery as local consolidative therapy was associated with encouraging outcomes and should be considered for these patients.

Survival benefit of local consolidative therapy for patients with single-organ metastatic pancreatic cancer: a propensity score-matched cross-sectional study based on 17 registries.

The continuous exploration of oligometastatic disease has led to the remarkable achievements of local consolidative therapy (LCT) and favorable outcomes for this disease. Thus, this study investigated the potential benefits of LCT in patients with single-organ metastatic pancreatic ductal adenocarcinoma (PDAC). Patients with single-organ metastatic PDAC diagnosed between 2010 - 2019 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was performed to minimize selection bias. Factors affecting survival were assessed by Cox regression analysis and Kaplan-Meier estimates. A total of 12900 patients were identified from the database, including 635 patients who received chemotherapy combined with LCT with a 1:1 PSM with patients who received only chemotherapy. Patients with single-organ metastatic PDAC who received chemotherapy in combination with LCT demonstrated extended median overall survival (OS) by approximately 57%, more than those who underwent chemotherapy alone (11 vs. 7 months, p < 0.001). Furthermore, the multivariate Cox regression analysis revealed that patients that received LCT, younger age (< 65 years), smaller tumor size (< 50mm), and lung metastasis (reference: liver) were favorable prognostic factors for patients with single-organ metastatic PDAC. The OS of patients with single-organ metastatic pancreatic cancer who received LCT may be prolonged compared to those who received only chemotherapy. Nevertheless, additional prospective randomized clinical trials are required to support these findings.

OA22.04 BRIGHTSTAR Local Consolidative Therapy with Brigatinib in Tyrosine Kinase Inhibitor-Naïve ALK-Rearranged Metastatic NSCLC

OA22.04 BRIGHTSTAR Local Consolidative Therapy with Brigatinib in Tyrosine Kinase Inhibitor-Naïve ALK-Rearranged Metastatic NSCLC

EP09.02-03 A Phase II Study on Aggressive Local Consolidative Therapy in Combination With Chemotherapy for Oligometastic NSCLC: TORG1529

EP09.02-03 A Phase II Study on Aggressive Local Consolidative Therapy in Combination With Chemotherapy for Oligometastic NSCLC: TORG1529

Oligo-Residual Disease in PD-1/PD-L1 Inhibitors Treated Metastatic Non-Small Cell Lung Cancer: Incidence, Pattern of Failure and Clinical Value of Local Consolidative Therapy

Growing numbers of clinical trials are testing the efficacy of incorporating local therapy into programmed death receptor (ligand) 1 (PD-1/PD-L1) inhibitors in metastatic non-small cell lung cancer (NSCLC), but the optimal timing and patient selection are still controversial. We aimed to examine the patterns of maximum tumor response and treatment failure in PD-1/PD-L1 inhibitor-treated NSCLC, and explore the potential clinical value of local consolidative therapy (LCT) in those with oligo-residual disease (ORD). Metastatic NSCLC treated with PD-1/PD-L1 inhibitors in three academic centers from May 2018 to December 2021 were retrospectively reviewed and those derived clinical benefit, defined as having objective response or durable stable disease lasting≥6months, were finally enrolled. Patterns of tumor response and treatment failure were extensively analyzed. ORD was defined as residual tumor distribution limited to 3 organs and 5 lesions, otherwise was defined as multiple residual disease (MRD). Local therapies targeting the residual tumor lesions performed after PD-1/PD-L1 inhibitors initiation and before initial disease progression, were considered as LCT. The primary endpoints were the overall survival (OS) and progression-free survival (PFS). Of the 318 patients enrolled, ORD and MRD were documented in 122 (38.4%) and 196 (61.6%) patients, respectively. Those who developed ORD had a significantly longer OS than those with MRD (p = 0.006). The median time to best response was 4 months and more than 50% of the initial disease progression developed only from the residual tumor lesions, providing the preliminary rationale of LCT. Among the 122 patients with ORD, those receiving LCT (n = 39) had significantly longer PFS (p = 0.04) and OS (p<0.001) than those without LCT. Moreover, LCT remained one of the independent predictors of improved PFS and OS after Cox analyses. Local consolidative therapy seems to be feasible and may provide extra survival benefit for metastatic NSCLC patients with oligo-residual disease after PD-1/PD-L1 inhibitor treatment.

Perioperative and oncologic outcomes of pulmonary resection for synchronous oligometastatic non–small cell lung cancer: Evidence for surgery in advanced disease

ObjectivesRecent randomized trials have demonstrated a survival advantage with the use of local consolidative therapy in oligometastatic non–small cell lung cancer; however, the indications for and outcomes after pulmonary resection as a component of local consolidative therapy remain ill defined. We sought to characterize the perioperative and long-term survival outcomes among patients with resected oligometastatic non–small cell lung cancer. MethodsPatients presenting to a single center (2000-2017) with oligometastatic non–small cell lung cancer (≤3 synchronous metastases, intrathoracic nodal disease counted as a single site) who underwent resection of the primary tumor were retrospectively identified. Charts were reviewed, and demographic, clinical, pathologic, oncologic, and survival outcomes were recorded. Survival outcomes were analyzed from the date of surgery. ResultsA total of 52 patients met inclusion criteria, among whom most (38, 73.1%) were ever smokers, had nonsquamous tumors (48, 92.3%), had no intrathoracic nodal disease (33, 63.5%), and had 1 to 2 sites of metastases (49, 94.2%). The majority (41, 78.9%) received systemic therapy, predominantly in the neoadjuvant setting (24/41, 58.5%). After resection, there were no 30- or 90-day deaths. After a median follow-up of 94.6 months (95% CI, 69.0-139.1), 37 patients (71.2%) progressed and 38 patients (73.1%) died. Median postoperative progression-free survival and overall survival were 9.4 (5.5-11.6) months and 51.7 (22.3-65.3) months, respectively. ConclusionsPulmonary resection as a means of maximum locoregional control in oligometastatic non–small cell lung cancer is feasible and safe, and may be associated with durable long-term survival benefits. The frequency of systemic postoperative progression highlights an urgent need to characterize perioperative and oncologic outcomes after pulmonary resection in the current era of novel systemic therapies.

Oligo-residual disease in PD-1/PD-L1 inhibitor-treated metastatic non-small cell lung cancer: Incidence, pattern of failure and clinical value of local consolidative therapy.

e21143 Background: Growing numbers of clinical trials are testing the efficacy of incorporating local therapy into programmed death receptor (ligand) 1 (PD-1/PD-L1) inhibitors in metastatic non-small cell lung cancer (NSCLC), but the optimal timing and patient selection are still controversial. We aimed to examine the patterns of maximum tumor response and treatment failure in PD-1/PD-L1 inhibitor-treated NSCLC, and explore the potential clinical value of local consolidative therapy (LCT) in those with oligo-residual disease (ORD). Methods: Metastatic NSCLC treated with PD-1/PD-L1 inhibitors in three academic centers from May 2018 to December 2021 were retrospectively reviewed and those derived clinical benefit, defined as having objective response or durable stable disease lasting≥6months, were finally enrolled. Patterns of tumor response and treatment failure were extensively analyzed. ORD was defined as residual tumor distribution limited to 3 organs and 5 lesions, otherwise was defined as multiple residual disease (MRD). Local therapies targeting the residual tumor lesions performed after PD-1/PD-L1 inhibitors initiation and before initial disease progression, were considered as LCT. The primary endpoints were the overall survival (OS) and progression-free survival (PFS). Results: Of the 318 patients enrolled, ORD and MRD were documented in 122 (38.4%) and 196 (61.6%) patients, respectively. Those who developed ORD had a significantly longer OS than those with MRD (p = 0.006). The median time to best response was 4 months and more than 50% of the initial disease progression developed only from the residual tumor lesions, providing the preliminary rationale of LCT. Among the 122 patients with ORD, those receiving LCT (n = 39) had significantly longer PFS (p = 0.04) and OS (p &lt; 0.001) than those without LCT. Moreover, LCT remained one of the independent predictors of improved PFS and OS after Cox analyses. Conclusions: Local consolidative therapy seems to be feasible and may provide extra survival benefit for metastatic NSCLC patients with oligo-residual disease after PD-1/PD-L1 inhibitor treatment.

Longitudinal tracking of ALK-positive lung cancer from plasma using circulating-tumor RNA and circulating-tumor DNA in the BRIGHTSTAR clinical trial.

e21072 Background: While the administration of specific tyrosine-kinase inhibitors (TKIs) in ALK-fusion positive lung cancer has led to significant improvement in clinical outcomes, detection of gene fusions remains challenging, especially from liquid biopsies. In tissue biopsies, assays which incorporate RNA-based detection have demonstrated increased sensitivity for gene fusion detection. We therefore hypothesized that a liquid biopsy assay equally including assessment of gene fusions using circulating-tumor RNA (ctRNA) in addition to circulating-tumor DNA (ctDNA), will improve detection. Furthermore, we hypothesized that detection of gene fusions as well as mutations will also correlate with clinical treatment. Methods: We retrospectively analyzed 89 samples from 35 patients included in the BRIGHTSTAR clinical trial assessing local consolidative therapy (LCT) and brigatinib in patients with stage IV or recurrent Non-small Cell Lung Cancer and confirmed ALK rearrangement (NCT03707938). Samples were included at baseline (N = 31), prior to LCT after 8 weeks of brigatinib treatment (N = 29), after LCT ( &lt; 3 weeks; N = 25) and at progression (N = 4). We used a targeted next generation sequencing (NGS) assay assessing both ctDNA as well as ctRNA (LiquidHALLMARK, Lucence Health, Palo Alto) to detect ALK fusions as well as mutations in 80 genes. Up to 5 ml of plasma was analyzed per sample. Results: At baseline, ALK fusions were detected in 15/31 patients (48%) of which 8 were detected using both ctDNA and ctRNA, while four were exclusively detected in ctDNA and three in ctRNA. Plasma ctDNA concentrations for patients with detectable ALK fusions at baseline were significantly higher than for those without detectable gene fusions (mean 26.1 ng/mL versus 16.6 ng/mL; p = 0.0044). ALK fusions were detected in two patients pre-LCT, exclusively in ctRNA, while ALK fusions cleared completely post-LCT. At progression, ALK fusions were detected in 2/4 samples (50%) in both ctDNA and ctRNA. Of the two negative samples tissue biopsies were available confirming the absence of an ALK rearrangement, including one transformation to squamous cell carcinoma. Overall, including analysis of ctRNA led to a 36% relative additional detection of ALK fusions compared to analyzing ctDNA alone. Furthermore, ctDNA mutation positivity in genes other than ALK was 17/31 (55%), 9/29 (31%), 8/25 (32%) and 3/4 (75%) for baseline, pre-LCT, post-LCT and progression, respectively. Conclusions: We highlight that ALK fusions can be reliably detected in plasma of lung cancer patients and detectability of ALK fusions correlate with exposure to treatment. Analyzing ctRNA in addition to ctDNA improves sensitivity of fusion detection and is a highly promising strategy in this setting.

20 Phase II randomized study of osimertinib (OSI) with or without local consolidative therapy (LCT) for metastatic EGFR mutant non-small cell lung cancer (NSCLC): Analysis of adverse events (AEs)

20 Phase II randomized study of osimertinib (OSI) with or without local consolidative therapy (LCT) for metastatic EGFR mutant non-small cell lung cancer (NSCLC): Analysis of adverse events (AEs)

Radiotherapy for Lung Metastases: Conventional to Stereotactic Body Radiation Therapy

The lung parenchyma and adjacent tissues are one of the most common sites of metastatic disease. Traditionally, the approach to treatment of a patient with lung metastases has been with systemic therapy, with radiotherapy being reserved for palliative management of symptomatic disease. The concept of oligo metastatic disease has paved the way for more radical treatment options, administered either alone or as local consolidative therapy in addition to systemic treatment. The modern-day management of lung metastases is guided by a number of factors, including the number of lung metastases, extra-thoracic disease status, overall performance status, and life expectancy, which all help determine the goals of care. Stereotactic body radiotherapy (SBRT) has emerged as a safe and effective method in locally controlling lung metastases, in the oligo metastatic or oligo-recurrent setting. This article outlines the role of radiotherapy in multimodality management of lung metastases.

Local Consolidative Therapy May Have Prominent Clinical Efficacy in Patients with EGFR-Mutant Advanced Lung Adenocarcinoma Treated with First-Line Afatinib

Afatinib is an irreversible tyrosine kinase inhibitor (TKI) targeting the epidermal growth factor receptor (EGFR), which is utilized for the treatment of patients with advanced lung cancer that harbors EGFR mutations. No studies have evaluated the clinical efficacy of LCT in patients treated with first-line afatinib. In this study, we retrospectively enrolled patients with advanced lung adenocarcinomas harboring susceptible EGFR mutations who were diagnosed and treated with first-line afatinib in three hospitals. A total of 254 patients were enrolled, including 30 (12%) patients who received LCT (15 patients received definitive radiotherapy for the primary lung mass and 15 patients received curative surgery). Patients who received LCT had a significantly longer PFS than those who did not (median PFS: 32.8 vs. 14.5 months, p = 0.0008). Patients who received LCT had significantly longer OS than those who did not (median OS: 67.1 vs. 34.5 months, p = 0.0011). Multivariable analysis showed LCT was an independent prognostic factor for improved PFS (adjusted hazard ratio [aHR] [95% confidence interval (CI)]: 0.44 [0.26-0.73], p = 0.0016) and OS (aHR [95% CI]: 0.26 [0.12-0.54], p = 0.0004). The analyses using propensity score-weighting showed consistent results. We conclude that LCT may improve clinical outcomes, in terms of PFS and OS, in patients with advanced EGFR-mutant lung adenocarcinomas who are treated with first-line afatinib.

Genomic features and its potential implication in bone oligometastatic NSCLC

ObjectivesEmerging evidence have demonstrated that oligometastatic non-small cell lung cancer (NSCLC) can achieve clinical benefit from local consolidative therapy. Bone oligometastasis is common in advanced lung cancer, but little is known about its molecular features. The purpose of our study aimed to investigate the genomic landscape bone oligometastatic NSCLC.MethodsWe collected paired blood and tissue samples from 31 bone oligometastatic NSCLC patients to make a comprehensive analysis of mutations by performing next-generation sequencing.ResultsA total of 186 genomic mutations were detected from 105 distinct cancer-relevant genes, with a median number of 6 alterations per tumor. The most frequently mutated genes were EGFR (58%) and TP53 (55%), followed by KRAS (16%), CDKN2A (13%) and MET (13%). The signatures related to smoking, aging, homologous recombination deficiency and APOBEC were identified as the most important mutational processes in bone oligometastasis. The median tumor mutation burden was 4.4 mutations/Mb. Altogether, genetic alterations of bone oligometastasis are highly targetable that 74.19% of patients had at least one actionable alteration that was recommended for targeted therapy based on the OncoKB evidence. Of these patients, 16.13% had two actionable alterations that could potentially benefit from a different combination of targeted drugs to achieve better outcomes.ConclusionOur research comprehensively elucidates the genomic features of bone oligometastatic NSCLC patients, which may optimize individualized cancer treatment in the era of precision medicine.

Benchmarking Outcomes for Molecularly Characterized Synchronous Oligometastatic Non-Small-Cell Lung Cancer Reveals EGFR Mutations to Be Associated With Longer Overall Survival.

Local consolidative therapy (LCT) for patients with synchronous oligometastatic non-small-cell lung cancer is an evolving treatment strategy, but outcomes following LCT stratified by genetic mutations have not been reported. We sought to identify genomic associations with overall survival (OS) and progression-free survival (PFS) for these patients. We identified all patients presenting between 2000 and 2017 with stage IV non-small-cell lung cancer and ≤ 3 synchronous metastatic sites. Patients were grouped according to mutational statuses. Primary outcomes included OS and PFS following initial diagnosis. Of 194 included patients, 121 received comprehensive LCT to all sites of disease with either surgery or radiation. TP53 mutations were identified in 40 of 78 (55%), KRAS in 32 of 95 (34%), EGFR in 24 of 109 (22%), and STK11 in nine of 77 (12%). At median follow-up of 96 months, median OS and PFS were 26 (95% CI, 23 to 31) months and 11 (95% CI, 9 to 13) months, respectively. On multivariable analysis, patients with EGFR mutations had lower mortality risk (hazard ratio [HR], 0.53; 95% CI, 0.29 to 0.98; P = .044) compared with wild-type patients, and patients with STK11 mutations had higher risk of progression or mortality (HR, 2.32; 95% CI, 1.12 to 4.79; P = .023) compared with wild-type patients. TP53 and KRAS mutations were not associated with OS or PFS. Among 71 patients with known EGFR mutational status who received comprehensive LCT, EGFR mutations were associated with lower mortality compared with wild-type (HR, 0.45; 95% CI, 0.22 to 0.94; P = .032). When compared with wild-type patients, those with EGFR and STK11 mutations had longer OS and shorter PFS, respectively. EGFR mutations were associated with longer OS among oligometastatic patients treated with comprehensive LCT in addition to systemic therapy.

Definitive Local Consolidative Therapy for Oligometastatic Solid Tumors: Results from the Lead-In Phase of the Randomized Basket Trial EXTEND

<h3>Purpose/Objective(s)</h3> The benefit of local consolidative therapy (LCT) for oligometastasis across histologies is undefined. EXTernal beam radiation to Eliminate Nominal metastatic disease (EXTEND; NCT03573611) is a phase II basket trial randomizing patients with 1-5 metastatic sites to standard of care (SOC) systemic therapy with or without LCT. We hypothesized that patients treated with LCT would have superior progression-free survival (PFS). Prior to the randomization phase of this trial, we initiated a single-arm lead-in component to evaluate enrollment feasibility and identify histology baskets most likely to complete accrual. Here we report the accrual, efficacy, and toxicity results of the lead-in phase. <h3>Materials/Methods</h3> Eligible histologies included colorectal, sarcoma, lung, head and neck, ovarian, kidney, melanoma, pancreatic, prostate, cervix/uterine, breast, and cholangiocarcinoma. All patients were treated with SOC systemic therapy plus LCT to all sites of active metastatic disease and primary/regional disease (as applicable). Enrollment in the lead-in phase was capped after 6 months, or for an individual histology, after accrual of 8 patients with that histology. Definitive LCT included surgery or radiation. Dose, fractionation, and systemic therapy were per oncologist discretion. PFS was defined by radiographically (RECIST v1.1), biochemically (prostate only), or clinically or by death, and was estimated by the Kaplan-Meier method. Common Terminology Criteria for Adverse Events v4.0 was used. <h3>Results</h3> From August 2018 through January 2019, 49 patients were enrolled and received LCT. The average age was 63 (range: 32-86). Data cutoff was February 14, 2022. Thirty-six patients had progression and 13 died. The median follow-up time for censored patients was 38 months (range 16-42 months). Prostate (n=8), breast (n=8), and kidney (n=7) represented the most common histologies. Many patients had one metastasis (53%), and 86 total lesions were treated. The most common LCT modality was radiation (97%), which was typically stereotactic (63%). Local control rate was 98% (n=84/86 tumors). Median PFS time was 13 months (95% CI 9–24), and 3-year overall survival rate was 73% (95% CI 57%–83%). Most progression events were new lesions outside the irradiated field (n=30, 83%). Grade 3 toxicity rate was 4% (n=2) and no grade 4+ toxicities were observed. <h3>Conclusion</h3> The prospective lead-in phase of EXTEND demonstrated feasibility of rapid accrual to a multi-histology basket trial, encouraging PFS, and low rates of severe toxicity at mature follow-up. The randomized phase is ongoing with histology-based baskets, which will provide histology-specific evidence to guide the application of LCT in oligometastatic disease.

1st Line Pembrolizumab in Treatment of Stage IV NSCLC Patients – A Pattern of Failure Analysis with Associated Survival Outcomes

<h3>Purpose/Objective(s)</h3> To investigate patterns of failure in metastatic NSCLC patients treated with pembrolizumab and analyze factors associated with oncologic outcomes. By discerning these patterns, a subset of patients could be identified that may benefit from local consolidative therapy. <h3>Materials/Methods</h3> This retrospective analysis included 118 patients diagnosed with metastatic NSCLC from January 2015 to May 2020 at a single institution. Each patient received at least one cycle of pembrolizumab and had radiographic follow up of at least 3 months. Patterns of failure were identified by first radiographic disease progression event after initiation of pembrolizumab. Initial failures were grouped by site of first progression (local (L), regional (R), distant (D), or any synchronous combination of the three (L+/-R+/-D)) as well as pattern of progression (existing lesions only (E), new lesions only (N), or both (B)). Descriptive statistics were used to report patterns of failure. Kaplan-Meier method, log-rank test, and Cox proportional hazard model were used to calculate OS/PFS outcomes, compare subgroups, and analyze patient characteristics for significance. <h3>Results</h3> Median follow up was 8.6 months. The majority of patients presented with synchronous and poly-metastatic (>5 metastases) disease (86% and 70%, respectively). Overall, 71 patients (60%) demonstrated progression. The most common site of first failure was a combination of local, regional, and/or distant progression (51%) and the most common pattern was progression at an existing lesion alone (42%) or at both a new and existing lesion (42%). By anatomical location of first progression, the majority of progression events occurred in existing locoregional lesions: 26 lung events and 24 regional LN (mediastinal/hilar) events. Median time to treatment failure was 4.6 months. Median OS and PFS for the entire cohort were 15.8 and 7.3 months, respectively. Median OS was 41.7 (no progression) vs 12.6 (progression) months (p<0.0001). Stratified by site/pattern of failure, only OS (L: 15.8 mo, R: 21.6 mo, D: 14.3 mo, combination 8.2 mo (p=0.001) and E: 12.6 mo, N: 22.2 mo, B: 8.5 mo (p=0.004)) was statistically significant. Median OS was significantly improved in patients who experienced oligoprogression vs systemic progression (19.4 vs 8.5 mo, p<0.0001). On UVA, only history of prior systemic therapy (OS and PFS) and intracranial disease at initial time of diagnosis (PFS only) were significant. On MVA, age < 65 (OS only), history of prior systemic therapy (OS and PFS), lower N stage (PFS only), and intracranial disease (PFS only) were found to be significant. <h3>Conclusion</h3> As the paradigm for treating metastatic NSCLC patients continues to evolve, elucidating patterns of failure and the factors associated with it can aid in identifying those who would benefit from additional (and potentially aggressive) local therapy. Further investigation is warranted.

Local Consolidative Therapy for Oligometastatic Non-Small Cell Lung Cancer.

Simple SummaryMetastatic non-small cell lung cancer (NSCLC) classically portends a poor prognosis and worse overall survival. However, recent advances in modern systemic therapy and the increasing recognition of a distant clinical entity known as “oligometastatic disease”—i.e., a controlled primary tumor and a limited number of distant lesions (≤5 metastases)—have led to paradigm shifts in management. Findings from Phase II randomized clinical trials suggest that aggressive local consolidative therapy (LAT) in the form of surgery or highly conformal radiation, known as stereotactic ablative body radiotherapy (SABR), may help to significantly mitigate disease progression and prolong survival. In this review, we summarize clinical evidence from published and ongoing trials that support the use of LAT/SABR in the treatment of oligometastatic NSCLC. We discuss key findings and caveats to these studies, and we highlight potential considerations and avenues for further investigation in the oligometastatic disease space.In the last 20 years, significant strides have been made in our understanding of the biological mechanisms driving disease pathogenesis in metastatic non-small cell lung cancer (NSCLC). Notably, the development and application of predictive biomarkers as well as refined treatment regimens in the form of chemoimmunotherapy and novel targeted agents have led to substantial improvements in survival. Parallel to these remarkable advancements in modern systemic therapy has been a growing recognition of “oligometastatic disease” as a distinct clinical entity—defined by the presence of a controlled primary tumor and ≤5 sites of metastatic disease amenable to local consolidative therapy (LAT), with surgery or stereotactic ablative body radiotherapy (SABR). To date, three randomized studies have provided clinical evidence supporting the use of LAT/SABR in the treatment of oligometastatic NSCLC. In this review, we summarize clinical evidence from these landmark studies and highlight ongoing trials evaluating the use of LAT/SABR in a variety of clinical contexts along the oligometastatic disease spectrum. We discuss important implications and caveats of the available data, including considerations surrounding patient selection and application in routine clinical practice. We conclude by offering potential avenues for further investigation in the oligometastatic disease space.

Role of Local Treatment for Oligometastasis: A Comparability-Based Meta-Analysis.

PurposeWe intend to investigate the oncological efficacy and feasibility of local consolidative therapy (LCT) through a meta-analysis method.Materials and MethodsFour databases including PubMed, MEDLINE, Embase, and Cochrane library were searched. Target studies are controlled trials comparing outcomes of LCT versus a control group. Primary endpoints are overall survival (OS) and progression-free survival (PFS).ResultsA total of 54 studies involving 7,242 patients were included. Pooled analyses showed that the LCT arm could achieve improved OS with pooled odds ratio of 2.896 (95% confidence interval [CI], 2.377 to 3.528; p < 0.001). Regarding PFS, pooled analyses showed pooled odds ratio of 3.045 (95% CI, 2.356 to 3.937; p < 0.001) in favor of the LCT arm. In the subgroup analyses including the studies with reliable comparability (e.g. randomized studies or intentionally matched studies without significant favorable prognosticator in LCT arms), pooled odds ratio was 2.548 (95% CI, 1.808 to 3.591; p < 0.001) favoring the LCT arm regarding OS. Regarding PFS, pooled OR was 2.656 (95% CI, 1.713 to 4.120; p < 0.001) which also favored the LCT arm. Subgroup analyses limited to the randomized controlled trials (RCT) were also performed and pooled odds ratios on OS and PFS were 1.535 (95% CI, 1.082 to 2.177; p=0.016) and 1.668 (95% CI, 1.187 to 2.344; p=0.003). The rates of grade ≥ 3 complications related to LCT was mostly low (< 10%) and not significantly higher compared to the control arm.ConclusionPooled analyses results of all included studies, selected studies with reliable comparability, and RCT’s demonstrated the survival benefit of LCT. These consistent results suggest that LCT was beneficial to the patients with oligometastasis.