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ES21 - Current Strategies to Improve Outcome of Patients with Oligometastatic NSCLC (ID 24)
- Event: WCLC 2019
- Type: Educational Session
- Track: Oligometastatic NSCLC
- Presentations: 5
- Now Available
The role of imaging in oligometastatic disease in NSCLC:
The current guidelines include a contrast-enhanced CT of the chest and upper abdomen as the baseline imaging investigation of lung cancer patients. A contrast-enhanced CT or MRI of the brain is indicated in patients who present with neurological signs/symptoms1. An additional investigation with PET-CT and MRI could be considered, "but only if their results could alter the treatment strategy"2. Lung cancer patients who are candidates to a radical treatment should be referred to a PET-CT if the initial investigations indicate a potentially curable disease2. Not infrequently, the identification of unsuspected metastasis on the PET-CT changes the initial staging to a stage IV, in a significant number of cases. A radical treatment can be considered for those with oligometastatic disease (OMD), which is defined by the National Cancer Institute as: "a small number of metastatic tumors in one or two other parts of the body"3. Discerning additional lung lesions as benign or malignant can be improved with the use of MRI4,5. Considering the limitations of PET-CT for detecting brain and liver metastases, MRI should be considered to avoid a futile extended radical treatment in this select group of patients5. This presentation will discuss the role of imaging in OMD patients being considered for extended radical treatment.
1. NICE. https://www.nice.org.uk/guidance/ng122/chapter/Recommendations#diagnosis-and-staging
2. Planchard D. et al. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology (2018) 29(4): iv192–iv237.
3. NCI. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/oligometastasis.
4. Basso Dias A. et al. Fluorine 18–FDG PET/CT and diffusion-weighted MRI for malignant versus benign pulmonary lesions: a meta-analysis. Radiology (2019) 290:525–534
5. Hochhegger B. et al. MRI in lung cancer: a pictorial essay. BJR (2011) 84:1003, 661-668
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ES21.02 - Biological Disease Characterization of OMD (Now Available) (ID 3270)
15:45 - 17:15 | Presenting Author(s): David E. Gerber
Variation in the characterization of OMD Trial OMD characteristics OMD timing Iyengar et al (2017)
· ≤6 sites of extracranial disease (including primary)
· ≤3 sites in liver or lung·Up to 2 contiguous vertebral metastases considered a single site
After first-line therapy and without progression Gomez et al (2016)
· ≤3 metastatic sites
· Any N1-3 thoracic nodes considered a single site· Satellite lesions counted as separate sites
After first-line therapy and without progression Parikh et al (2014) · ≤5 metastatic sites After first-line therapy and without progression Cheruvu et al (2011) · ≤8 metastatic sites At time of initial staging Khan et al (2006)
· 1-2 metastatic sites· Definitive (surgery and/or chemoradiation) treatment of thoracic disease
After treatment of thoracic disease
Recent years have seen a marked increase in interest in the concept of oligometastatic disease (OMD) in non-small cell lung cancer (NSCLC). Lacking a precise and consistent definition, OMD is generally considered to represent a relatively favorable clinical state, with more indolent biology, a limited number of disease sites, and potential for prolonged periods of disease control. Discussions of oligometastatic NSCLC area inexorably linked with management considerations, specifically the use of local therapies such as surgery and radiation therapy. There are numerous clinical and biological rationales to support such approaches: (1) disease progression most commonly occurs in original sites of gross disease1; (2) metastatic sites may propagate secondary metastases (parallel progression model)2; (3) solid tumors are composed of faster growing (sensitive) and slower growing (resistant) cell populations (Norton-Simon hypothesis)3; (4) resistance depends on spontaneous mutations and therefore increases with time (Goldie-Coldman hypothesis).4
Nevertheless, several questions regarding the characterization and optimal management of OMD remain (Table 1). Up to how many sites of disease constitute an oligometastatic state? Does a “site” of disease comprise a single lesion or neighboring tumors? Does the anatomic site matter? For instance, brain metastases have historically been considered a more favorable location for definitive treatment of OMD, and their emergence may reflect pharmacokinetic failure rather than molecular evolution.5,6 Additionally, there are likely meaningful clinical differences between OMD states depending on whether they are defined at diagnosis (de novo), after initial exposure to systemic therapy (induced), recurrence, or progression.
OMD may also have a distinct biologic phenotype. The metastatic cascade includes loss of cellular adhesion, increased motility, primary tumor invasiveness, entry into and survival in the circulation, and entry into and colonization of distant organs.7 Tumor dormancy, regulated in part by interferon signaling, may impact the number, location, and timing of metastases.8 Expression of genes that positively regulate the cell cycle may determine whether cancer growth occurs as polymetastasis versus oligometastasis. Ideally, ongoing and future clinical trials will collect biospecimens for discovery and validation of OMD biomarkers, thereby enabling the identification of cases most likely to benefit from OMD treatment paradigms.
1. Rusthoven KE, Hammerman SF, Kavanagh BD, Birtwhistle MJ, Stares M, Camidge DR. Is there a role for consolidative stereotactic body radiation therapy following first-line systemic therapy for metastatic lung cancer? A patterns-of-failure analysis. Acta Oncol 2009;48:578-83.
2. Klein CA. Parallel progression of primary tumours and metastases. Nat Rev Cancer 2009;9:302-12.
3. Norton L, Simon R. Tumor size, sensitivity to therapy, and design of treatment schedules. Cancer Treat Rep 1977;61:1307-17.
4. Goldie JH, Coldman AJ. A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 1979;63:1727-33.
5. Hu C, Chang EL, Hassenbusch SJ, 3rd, et al. Nonsmall cell lung cancer presenting with synchronous solitary brain metastasis. Cancer 2006;106:1998-2004.
6. Grommes C, Oxnard GR, Kris MG, et al. "Pulsatile" high-dose weekly erlotinib for CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol 2011;13:1364-9.
7. Gupta GP, Massague J. Cancer metastasis: building a framework. Cell 2006;127:679-95.
8. Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nature reviews Immunology 2006;6:836-48.
ES21.03 - Interpreting the Current Data for Local Consolidative Treatment in the Setting of Oligometastatic Disease: Where Do We Stand? (Now Available) (ID 3271)
15:45 - 17:15 | Presenting Author(s): Daniel Gomez
Over the past 15 years, several retrospective and single arm prospective studies suggested a benefit for local consolidative therapy (surgery, radiation therapy, or interventional radiologic ablation) in the setting of oligometastatic disease. More recently, a small number of randomized trials have provided further data regarding the utility of an agressive approach with regard to progression free and overall survival. With the considerable amount of emerging evidence, it can be difficult to aggregate and interpret the major themes across studies. This presentation will discuss the composite data of local consolidative therapy in oligometastases, with a particular focus on high impact non-randomized studies and the limited randomized trials addressing this topic. The presentation will then provide major conclusions that can be the basis for analysis going forward. Attendees will thus be provided with a summary of the current evidence in the oligometastatic disease context and a basis for future directions.
ES21.04 - Optimal Systemic Treatment of OMD (Now Available) (ID 3272)
15:45 - 17:15 | Presenting Author(s): Hideo Kunitoh
A series of randomized trials (1-3), 2 of them specifically conducted for non-small cell lung cancer (NSCLC) patients (2,3), have shown that those with OMD could get clinical benefit from the addition of local ablative therapy to the standard systemic treatment. All 3 trials demonstrated improvement of progression-free survival (PFS), and 2 of them suggested overall survival (OS) benefit (1,2). OS was the primary endpoint of the 2 studies.
In each of the trials, however, the “standard systemic treatment” was not specified; in fact, it was merely described that the systemic therapy was determined by the treating oncologists from a set of “standard-of-care options” (3). It would be easy to imagine that the “standard-of-care options” for OMD in these trials would be no different from those for other stage IV diseases.
For NSCLC, they are cytotoxic chemotherapies according to histologic subtypes, appropriate target-based therapies when the tumors have druggable targets, and, more recently, immune-oncology (IO) drugs when the tumors have potentially predictive markers, such as PD-L1 (4) or tumor mutation burdens (5). The question is, is the optimal systemic therapy of OMD really exactly same with the “standards” of other, more advanced, poly-metastatic stage IV NSCLC?
First of all, let me suppose that the disease is truly oligo-metastatic, meaning there are no other metastatic foci than those which are detected by the image scans. In this scenario, you do not require systemic therapy at all; the disease is “cured” by a series of local ablative therapies, since no other diseases exist.
However, in the vast majority of the patients, this would not be the case. Instead, there should be some other “microscopic” metastases which are undetected by the scans, evade the local therapies, and get relapsed without systemic treatment. By focusing on the “microscopic metastases” status, you could make analogy to post-operative adjuvant therapy.
After the apparently curative surgery, without no “macroscopic” metastases in sight, we usually use conventional chemotherapies for prevention of recurrence. It is hoped that these “cytotoxic” drugs would eradicate the residual cancer cells, leading to true “cures”. The long-tails of the survival curves, with increased number of long-term survivors with the adjuvant chemotherapy (6), show that this theory actually works.
On the other hand, use of target-based drugs as post-operative adjuvant therapy has so far had only limited success (7,8). The PFS is elongated, without OS benefit (7). It appears that the patients do as good with the use of “targeted” drugs after relapse, and those drugs suppress tumors only as long as they are taken (9). In other words, they appear “cytostatic” and unable to “cure” the disease. Results of IO adjuvant trials are not yet available, but the “long-tails” of the survival curves of IO treatment make us hope for strong cytotoxic, “cure-oriented” effect.
Therefore, when you aim at “cure” of the OMD, you should choose cytotoxic chemotherapies and/or IO drugs. However, if you are to “control” the disease and get some OS improvement, target-drugs are strong candidates.
Let me see the topic from another viewpoint. The “local ablative” therapies employed in OMD are surgery and (stereotactic) radiotherapy. Which systemic therapy would make a better partner to which local therapy?
Almost all target drugs are eventually turned ineffective, due to acquired resistance. However, in some cases, you could elucidate the resistance mechanism and conquer it (10), with modification of the target-based “precision” medicine.
At present, investigation of the tumor itself is the most certain method, as expressed in the “tissue is the issue” slogan. Very often, however, tiny pathological specimens obtained from transbronchial or CT-guided biopsies are insufficient for the full molecular analysis. Surgical resection of the tumor has advantages both in terms of curative therapy and supply of ample specimens. It also minimizes the late effect on pneumonitis, which is a rare but dreadful toxicity of target-based tyrosine kinase inhibitors. Taken together, use of surgery would be (more) appropriate when you use target-based drugs in OMD.
On the other hand, there are some clinical data that prior use of radiotherapy is associated with better outcome of IO therapy, implying the so-called “abscopal” effect (11). Investigations are on-going, which are aimed at showing synergistic effect of stereotactic radiotherapy and IO treatment (12,13). This could be applied in the management of OMD.
So, in conclusion, what is the optimal systemic treatment of OMD? It depends on the aim of the therapy, cure vs elongation of PFS/OS, as well as on the choice of main local therapy, surgery vs radiotherapy. Future studies should specify the aim of the clinical investigation, not only to maximize the efficacy of local therapies and benefit to the patients, but to increase the statistical power of the clinical trials.
1. Palma DA, et al. Lancet 2019
2. Gomez DR, et al. J Clin Oncol 2019
3. Iyenger P, et al. JAMA Oncol 2018
4. Sacher AG, Gandhi L. JAMA Oncol 2016
5. Goto Y. J Clin Oncol 2018
6. Pignon J-P, et al. J Clin Oncol 2008
7. Kelly K, et al. J Clin Oncol 2015
8. Zhong WZ, et al. Lancet Oncol 2018
9. Pennell NA, et al. J Clin Oncol 2019
10. Jänne PA, et al. New Engl J Med 2015
11. Shaverdian N, et al. Lancet Oncol 2017
12. Luke JJ, et al. J Clin Oncol 2018
13. Miyamoto S, et al. Jpn J Clin Oncol 2019
ES21.05 - Clinical Trials to Advance the Field of OMD (Now Available) (ID 3273)
15:45 - 17:15 | Presenting Author(s): Thierry Berghmans
Oligometastatic disease (OMD) in non-small cell lung cancer (NSCLC) is a complex pathology. Four settings can be displayed where synchronous OMD (sOMD), occurring at the time of initial diagnosis, was the most evaluated in clinical trials. Other potential situations are oligorecurrence (rOMD), developed after optimal local control of a localised tumour, oligoprogression (pOMD) corresponding to a progression in a limited number of metastatic sites, and oligopersistant disease (peOMD) after/on systemic therapy. Several non-randomised phase II studies demonstrated the feasibility adding local ablative therapy (LAT) to systemic therapy in sOMD. Design, number of metastatic sites, type of LAT (chemoradiotherapy [CTRT], surgery, stereotactic radiotherapy [SBRT]) and endpoints largely differed among studies. A first pilot study (1) showed that surgery at the primary and the single metastatic sites after induction chemotherapy (CT) was feasible with 57% complete resection (R0) and 11 months median survival (MST). The same approach was recently confirmed in another prospective study with 71% R0 and 46.5% 5-years survival (2). Later, a phase II study conducted in The Netherlands and recently updated (3) demonstrated, when combining LAT (surgery or radiotherapy) to systemic therapy, MST of 13.5months but more essential, 5 and 6-years survival rates of 7.7% and 5.1% respectively. Other phase II studies, including NSCLC with <6 metastases, confirmed those results whether considering overall survival (4), metabolic response (5) or progression-free survival (PFS) (6).
The first randomised phase II trial (RCT) compared, in sOMD with < 3 metastases non-progressing after CT, LAT (surgery, SBRT, CTRT) plus maintenance to maintenance only. The study closed early after first interim analysis and 49 randomised patients. Updated data confirmed improved PFS (14.2 months vs 4.4 months; p = 0.022) and MST (41.2 months vs 17 months; p = 0.017) favouring the LAT arm. A second small-sized phase II RCT closed early after interim analysis (8). 29 sOMD patients (≤5 metastases) not progressing after CT were randomised between SBRT plus maintenance or maintenance. Also median PFS improved from 3.5 months to 9.7 months (p = 0.01) in the LAT arm.
All these data need confirmation in larger RCT. Four phase III trials are or will be ongoing. SARON (NCT02417662) is comparing standard CT alone to CT plus SBRT in sOMD with ≤ 3 metastases. In the OMEGA trial (NCT03827577), patients with synchronous or metachronous oligometastatic NSCLC (1-3 metastatic lesions) were considered for LAT (surgery or RT) or not in addition to systemic therapy. SINDAS (NCT02893332) is assessing the role of SBRT in addition to tyrosine kinase inhibitor in sOMD EGFR muted NSCLC with ≤ 5 tumoral sites (inclusive primary site; lymph nodes being considered as a metastatic site). Finally, HALT (NCT03256981) is a phase II-III RCT evaluating SBRT for pOMD during targeted therapy in NSCLC harbouring activating mutations.
All these studies are presenting with various designs and primary endpoints, but also differences in staging procedures resulting in major difficulties for definite conclusions on the usefulness of LAT in OMD patients. In order having similar populations among clinical trials, we need that a common definition is used by all investigators. In this way, the EORTC Lung Cancer Group proposed a definition for sOMD based on a consensus from thoracic oncology experts (8). Using common definition and staging assessment, and finding predictive factors for a better patient’s selection should be addressed in future clinical trials.
1. Downey et al. A phase II trial of chemotherapy and surgery for non-small cell lung cancer patients with a synchronous solitary metastasis. Lung Cancer 38:193-7, 2002
2. Endo et al. A prospective study of surgical procedures for patients with oligometastatic non-small cell lung cancer. Ann Thorac Surg 98:258-64, 2014.
3. De Ruysscher et al. PFS and OS beyond 5 years of NSCLC patients with synchronous oligometastases treated in a prospective phase II trial (NCT 01282450) OA07.07 J Thorac Oncol 2018
4. Arrieta et al. Radical consolidative treatment provides a clinical benefit and long-term survival in patients with synchronous oligometastatic non-small cell lung cancer: A phase II study. Lung Cancer. 130:67-75, 2019
5. Petty et al. Long-Term Outcomes of a Phase 2 Trial of Chemotherapy With Consolidative Radiation Therapy for Oligometastatic Non-Small Cell Lung Cancer. Int J Rad Oncol Biol Physics. 102:527-535, 2018.
6. Collen et al. Phase II study of stereotactic body radiotherapy to primary tumor and metastatic locations in oligometastatic nonsmall-cell lung cancer patients. Ann Oncol. 25:1954-9, 2014.
7. Gomez 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 JCO1900201, 2019.
8. Dingemans et al, MA25.02 Journal of Thoracic Oncology 2018;13:S445-S446
P2.18 - Treatment of Locoregional Disease - NSCLC (ID 191)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment of Locoregional Disease - NSCLC
- Presentations: 1
- Now Available
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
P2.18-01 - A Multicenter, Double-Blind, Randomized, Controlled Study of Bintrafusp Alfa (M7824) in Unresectable Stage III NSCLC (Now Available) (ID 2200)
10:15 - 18:15 | Author(s): Francoise Mornex
The TGF-β pathway promotes tumor immunosuppression, and its inhibition may enhance the antitumor activity of PD-(L)1 monoclonal antibodies and reduce radiation-induced lung fibrosis. Bintrafusp alfa is an innovative first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. In a phase 1 study, second-line bintrafusp alfa therapy demonstrated promising antitumor activity in advanced non-small cell lung cancer (NSCLC) (NCT02517398). In preclinical studies, bintrafusp alfa plus radiotherapy showed enhanced antitumor activity compared with radiotherapy alone in mouse models. This study is evaluating the efficacy and safety of bintrafusp alfa with concurrent chemoradiation (cCRT) followed by bintrafusp alfa vs cCRT plus placebo followed by durvalumab in patients with unresectable stage III NSCLC.Method
This global, multicenter, double-blind, randomized, controlled study of bintrafusp alfa (NCT03840902) includes adults with histologically documented stage III locally advanced, unresectable NSCLC, ECOG performance status ≤1, adequate pulmonary function, and life expectancy ≥12 weeks. Patients with tumors with actionable mutations (EGFR, ALK translocation, ROS-1 rearrangement) are also eligible. Mixed small cell lung cancer and NSCLC histology; pleural effusions greater than minimal, exudative, or cytologically positive; significant acute or chronic infections; prior chemotherapy or immune checkpoint inhibitor therapy for NSCLC; and current use of immunosuppressive medication are exclusion criteria. Patients are randomized to receive either bintrafusp alfa 1200 mg IV every 2 weeks (Q2W) with cCRT for 6 weeks followed by bintrafusp alfa 1200 mg IV Q2W (arm A) or placebo with cCRT for 6 weeks followed by durvalumab 10 mg/kg IV Q2W (arm B) until confirmed disease progression, unacceptable toxicity, or treatment ≤1 year. The primary endpoint is progression-free survival; secondary endpoints include overall survival, safety, lung function assessment, objective response, duration of response, pharmacokinetics, and immunogenicity. This phase 2 trial was activated on April 2, 2019 and first patient in is anticipated for May 22, 2019. Target enrollment: 350 patients.Result
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