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Mara B Antonoff
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ES03 - Understanding and Treating Oligometastatic Diseases (ID 161)
- Event: WCLC 2020
- Type: Educational Session
- Track: Locoregional and Oligometastatic Disease
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 10:30 - 11:30, Scientific Program Auditorium
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ES03.05 - Surgery as a Component of Local Consolidative Therapy (ID 3979)
10:30 - 11:30 | Presenting Author(s): Mara B Antonoff
- Abstract
- Presentation
Abstract
Historically, treatment for non-small cell lung cancer (NSCLC) has been stage-dependent, with surgery typically considered the standard of care for stage I disease and a potential component of multi-modality care for stages II-III. By contrast, for stage IV disease, therapy aimed at prolongation of life has included systemic treatments, including chemotherapy, and, in recent years, targeted agents and immunotherapy. For metastatic disease, surgery has previously had a fairly limited role. However, oligometastatic disease may offer a potential opportunity for more aggressive local options. The distinct tumor biology and limited disease burden may be associated with improved outcomes.1
The landmark oligometastatic trial published by Gomez in 20162 aimed to assess the effect of local consolidative therapy (LCT) on progression-free survival (PFS) of patients with 3 or fewer metastases who received standard first-line chemotherapy, and patients were randomized to LCT vs maintenance treatment. LCT improved PFS and time to development of new metastatic lesions. Moreover, comprehensive LCT (cLCT) was also shown to improve overall survival (OS).3 A subsequent review from our institution of 194 patients, including those both on and off the oligometastatic clinical trial, aimed to identify those patients who would derive greatest benefit from LCT.4 This study revealed that cLCT was associated with improved OS, with median survival of 29 months for cLCT compared to 23 months for those with subcomprehensive LCT or no LCT. Moreover, lower intrathoracic stage, non-squamous histology, and absence of bone metastases were all associated with improved OS after cLCT, theoretically identifying those patients most likely to benefit from aggressive local therapy—which can consist of surgery or radiation.
In terms of surgery itself, we next aimed to evaluate the outcomes of operative pulmonary resection as LCT in oligometastatic disease,5 using radiotherapy as a benchmark comparator. Evaluating patients with 3 or fewer synchronous metastases and received LCT to all sites, we analyzed survival and progression. Surgery to the primary tumor was performed in 28% after a median of 3.7 months. 90-day post-treatment mortality after surgery was 0%, and, after a median follow-up of 57 months, median OS after surgery was greater than 55 months. Median OS for radiation in this group was 23 months. Thus, it was concluded that surgery should remain a component of LCT for operable oligometastatic NSCLC patients, and it should be considered in randomized trial for patients with metastatic disease.
While surgery has demonstrated survival benefits in the oligometastatic population, the potential complexity of these procedures cannot be overstated. In our institutional experience, thoracotomies have been required in more than 4/5 of operations, and adhesions and hilar fibrosis have been common. Events such as need for proximal pulmonary arterial control and unplanned changes in extent of operation are not infrequent, and the majority of cases have been reported as more difficult than usual. Thus, proper patient selection for surgery is imperative, as is preparation for the types of resources potentially needed for these cases. Despite surgical complexity, ability to achieve negative margins and to safely manage the patients perioperatively has been reassuring.
Given the success of surgery as a component of LCT, surgery has become an important part of ongoing clinical trials evaluating LCT after novel agents for metastatic NSCLC. The LONESTAR trial6 aims to evaluate the benefits of LCT after immunotherapy, in that patients receive 12 weeeks of ipilumimab and nivolumab, after which those individuals with non-progressive disease are randomized to LCT + continued immunotherapy vs continued immunotherapy alone. While radiation is required to at least one disease site, surgery to the primary site of disease is emphasized whenever possible. Similar to the LONESTAR trial, the NORTHSTAR trial is investigating the role of LCT after tyrosine-kinase inhibitor therapy for patients with EGFR-mutant metastatic NSCLC. Patients who have non-progressive disease after 6-12 weeks of osimertinib are randomized to LCT vs continued targeted therapy, again, offering surgery whenever feasible to the primary site of disease.7 More recently, the BRIGHTSTAR trial was initiated, evaluating the role of LCT after 8 weeks of brigatinib for patients with metastatic ALK-mutated NSCLC, with the primary endpoints of safety and feasibility and secondary endpoints of PFS, OS, and time to progression.8 A number of patients have already undergone surgery on each of these trials, with promising perioperative outcomes.
Despite the potential for innovation and expanded surgical indications, consideration must be given to the safety and potential technical challenges in such cases. We must consider issues related to fibrosis, adhesions, and sclerotic lymph nodes, as well as our limitations in identifying those patients with residual disease vs complete response.
Surgery as LCT for oligometastatic NSCLC represents an exciting frontier for thoracic surgery, as a potential opportunity to help patients with advanced disease. Implications for training and resource allocation remain ever pertinent, and surgery needs to be considered as a potential therapeutic component in novel clinical trials in even advanced disease.
References:1. Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol. 1995 Jan;13(1):8-10.
2. Gomez DR et al. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. 2016 Dec;17(12):1672-1682.
3. Gomez DR et al. Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients With Oligometastatic Non-Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, Randomized Study. J Clin Oncol. 2019 Jun 20;37(18):1558-1565.
4. Mitchell KG et al. Improved Overall Survival With Comprehensive Local Consolidative Therapy in Synchronous Oligometastatic Non-Small-Cell Lung Cancer. Clin Lung Cancer. 2020 Jan;21(1):37-46.e7.
5. Mitchell KG et al. Pulmonary resection is associated with long-term survival and should remain a therapeutic option in oligometastatic lung cancer. J Thorac Cardiovasc Surg. 2020 Mar 25:S0022-5223(20)30633-4.
6. Phase III Trial of (LCT) After Nivolumab and Ipilimumab, https://clinicaltrials.gov/ct2/show/NCT03391869
7. Elamin YY et al. Randomized phase II trial of osimertinib with or without local consolidation therapy (LCT) for patients with EGFR-mutant metastatic NSCLC (NORTHSTAR). Annals of Oncology (2018)29 (suppl_8):viii493-viii547.
8. Elamin Y et al. BRIGHTSTAR: A pilot trial of local consolidative therapy (LCT) with brigatinib in tyrosine kinase inhibitor (TKI)-naïve ALK-rearranged advanced NSCLC.Journal of Clinical Oncology 2020 38:15_suppl, 9624-9624
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FP04 - Locoregional and Oligometastatic Disease (ID 126)
- Event: WCLC 2020
- Type: Posters (Featured)
- Track: Locoregional and Oligometastatic Disease
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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FP04.04 - EGFR Mutations Predict Superior Survival of NSCLC Patients with Oligometastatic Disease Treated with Local Consolidative Therapy (ID 2994)
00:00 - 00:00 | Author(s): Mara B Antonoff
- Abstract
Introduction
Local consolidative therapy (LCT) following systemic therapy for selected patients with oligometastatic non-small cell lung cancer (NSCLC) is an evolving treatment strategy. We sought to identify predictive genomic markers for overall survival (OS) and progression free survival (PFS) in patients presenting with synchronous oligometastatic NSCLC at diagnosis.
Methods
Patients presenting to a single institution (2000-2017) with stage IV NSCLC and ≤3 synchronous metastatic lesions were identified. Of 194 patients who met our inclusion criteria, 121 received comprehensive local consolidative therapy (LCT) to all sites of disease with either surgery or radiation. Intrathoracic nodal disease was counted as one site. Univariable and multivariable Cox regressions were performed to identify factors associated with OS. A ninety-day landmark analysis was performed to limit survivorship bias. Mutational status was obtained via an institutional database, when available.
Results
Of 194 patients who met our inclusion criteria and had genomic data available, TP53 mutations were identified in 40 of 55 (72%), KRAS in 30 of 65 (46%), EGFR in 22 of 90 (24%), ALK in 4 of 81 (5%), ROS1 in 2 of 63 (3%), and BRAF in 1 of 32 (3%) patients. The median age was 62 years. After a median follow-up of 52.3 months, median OS and PFS for this cohort was 26.5 (CI 23.0-30.0) months and 11.1 (95%, 9.1-13.0) months, respectively. Among all patients, comprehensive LCT to all sites of disease (N=121) was associated with improved OS (HR 0.67, CI 0.47-0.96, p=0.03) consistent with our previous study. Among all patients, on univariable analysis, patients with EGFR mutations had improved median OS (95.5 vs 37.2 months, p=0.03) compared to EGFR WT patients. Conversely, TP53, and KRAS mutations did not predict for OS. Among patients who received comprehensive LCT with known EGFR mutational status (N=57), EGFR mutations continued to predict for improved median OS (97.5 vs 29.8 months, p=0.02) (Figure 1).
Conclusion
Aggressive consolidative therapy to the primary lesion and all metastatic sites was associated with improved OS in a large cohort of oligometastatic patients, supporting results of recent prospective trials. EGFR mutations, but not KRAS or TP53 mutations, predicted for improved OS among oligometastatic patients who are treated with comprehensive LCT in addition to systemic therapy. These data support ongoing prospective trials evaluating the benefit of local therapy in oligometastatic EGFR mutant NSCLC.
