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Myung-Ju Ahn
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MS 13 - How to Deal with CNS Metastases (ID 535)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Martin Schuler, Nir Peled
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 502
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MS 13.05 - Targeted Therapy for EGFR Positive Mutant NSCLC with CNS Metastasis (ID 7703)
12:00 - 12:15 | Presenting Author(s): Myung-Ju Ahn
- Abstract
- Presentation
Abstract:
Central nervous system (CNS) metastases including brain metastasis (BM) and leptomeningeal metastasis (LM) are associated with poor prognosis in non-small cell lung cancer (NSCLC). The epidermal growth factor receptor (EGFR) mutations were initially reported in 2004 and currently defined the most prevalent actionable genomically classified subgroup of NSCLC, which account for 40% of Asian patients and 10-15% of White or African American patients. Patients with EGFR mutant NSCLC may have a higher incidence of CNS metastases due to prolonged survival with targeted agents and the increased quality of CNS imaging. More than 50% of NSCLC patients with EGFR mutation develop CNS metastases during their lifetime (1). The median overall survival (OS) for patients with BM is around 16 months (2) and 4.5-11 months for those with LM (3). Whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), or surgery is widely used for BM, whereas no standard therapy is available for LM. Moreover, the benefit of radiotherapy is limited due to toxicities and long term sequelae. Brain is a privileged site, sheltered from the systemic circulation by the blood-brain-barrier (BBB), which is highly specialized structure with tight junctions created by the interaction between astrocytes, pericytes and endothelium. In addition, numerous efflux transporters (e.g. P-glycoprotein) have been identified, leading to prevent many traditional drugs from the circulation into the brain parenchyma. Although the permeation of EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib or erlotinib across the BBB has been reported, the cerebrospinal fluid (CSF) concentrations of TKIs at standard doses comprise only small fraction of the plasma concentration indicating the limited ability to permeate into the CSF (4). Several small series of phase II studies reported that EGFR TKIs, gefitinib, erlotinib or afatinib show CNS response rate of 55 to 89%, median PFS of 5.8 to 14.5 months and median OS of 15.9 to 22.9 months in patients with brain metastases. Recently, new generation EGFR TKI, AZD 3759 which is designed to effectively penetrate BBB demonstrated profound anti-tumor activity in preclinical models. Phase I study showed the free plasma concentration of AZD 3759 was approximately at the same range as that in CSF and yielded K~p,uu~,~CSF~ values of 1.18 and 1.00 for 200mg and 300mg, respectively. Tumor responses were observed in 83% and 72% of the patients with CNS and extracranial disease respectively in EGFR TKI naïve NSCLC (5). Osimertinib, a third generation EGFR TKI designed to target both activating EGFR mutation and T790M but sparing wild type EGFR, distributed into mouse brain to a greater extent than gefitinib (brain/plasma ratio 3.4 for osimertinib vs 0.21 for gefitinib). Osimertinib showed significant brain exposure and tumor shrinkage in preclinical brain metastases model. In 50 of 411 evaluable for CNS response in pooled AURA phase II study, osimertinib showed 53% of response rate and the median CNS PFS has not been reached (6). Confirmatory phase III study comparing osimertinib with platinum-doublets in T790M positive patients demonstrated significant improvement of PFS regardless of CNS metastases suggesting this agent has benefit in patients with CNS metastases. Recently released press showed that first-line osimertinib comparing with gefitinib/erlotinib (FLAURA) met the primary endpoint of PFS. It would be interesting to evaluate whether upfront use of osimertinib in EGFR mutant NSCLC can delay CNS metastases. Given the relatively high response rate in brain metastasis with EGFR TKI, the upfront use of EGFR TKI can delay other local therapies such as WBRT, SRS or surgery, leading to reduced side effects related to local therapy. However, the retrospective multi-institutional analysis demonstrated that the use of upfront EGFR TKI and deferral of radiotherapy is associated with inferior OS in patients with EGFR mutant NSCLC who developed brain metastases (7). Based on the potential synergistic effects of the combination of EGFR TKIs and radiotherapy due to opening of BBB by radiotherapy, several prospective trials were conducted. A phase II study of erlotinib combined with WBRT in 40 patients with NSCLC achieved 86% of response rate, 11.8 months of overall survival, whereas 19.1 months in patients with EGFR mutation (8). The Radiation Therapy Oncology Group conducted a phase II trial of WBRT and SRS alone or with either temozolomide or erlotinib for NSCLC patients with one to three brain metastases (EGFR mutation status was not tested). This study was closed early due to slow accrual and three arms did not show any differences in terms of efficacy. However, grade 3 to 5 toxicities were 41-49% in two concurrent drug combination arms. Thus, prospective randomized trial of SRS followed by EGFR TKI vs EGFR TKI followed by SRS at CNS progression is needed. Leptomeningeal disease (LM) is a fatal manifestation and its incidence is increasing in EGFR mutant NSCLC up to 10%. The prognosis remains very poor despite systemic treatment, intrathecal chemotherapy, radiotherapy and even molecular targeted therapy. Although EGFR TKIs have shown promising efficacy in the treatment of LM, especially with high dose or pulsatile dosing, the duration of efficacy is still limited with lack of survival improvement (9). Compared to gefitinib, erlotinib showed higher CSF concentrations (28.7 vs 3.7 ng/ml) and retrospective analysis showed promising activity with erlotinib in LM. It is not clear whether combination of intrathecal chemotherapy or WBRT can be applied to EGFR mutant NSCLC patients. Given the significantly higher penetration across the BBB (K~p,uu,brain ~=0.86) of AZD 3759, AZD3759 showed 28% of response rate (5/18) in TKI pretreated LM patients and 75% (3/4) in TKI naïve patients suggesting promising efficacy. The mean osimertinib concentration in CSF was 7.5nM in the T790M unselected cohort and AZD 9291 at 160mg once daily demonstrated encouraging activity with 43% of LM disease response and manageable tolerability (10). Both agents are currently being investigated in a larger cohort of patients with brain metastasis and leptomeningeal disease. Another challenge of conducting clinical trial in patients with LM is lack of standardized response evaluation method. Combinational measurements including neurological sign, CNS imaging and CSF cytology have been proposed, but further validation is warranted. In conclusion, CNS metastases in EGFR mutant NSCLC are increasing. Although EGFR TKI has been reported to improve clinical outcome, isolated or pre-dominant progression of CNS metastases remains a major issue in patients on EGFR inhibitors due to relative low penetration to BBB. New generation EGFR TKIs with better BBB penetration might have an impact on therapeutic strategies. Further studies are required to evaluate the optimal sequence of EGFR TKI therapy and radiotherapy. References Rangachari D, , et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer 2015; 88: 108-11. Fan Y, Xu X, Xie C. EGFR-TKI therapy for patients with brain metastases from non-small-cell lung cancer: a pooled analysis of published data. Onco Targets Ther 2014; 7: 2075-84. Umemura S, Tsubouchi K, Yoshioka H, et al. Clinical outcome in patients with leptomeningeal metastasis from non-small-cell lung cancer: Okayama Lung Cancer Study Group. Lung Cancer 2012; 77: 134-9. Togashi Y, Masago K, Masuda S, et al. Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer. Cancer Chemother Pharmacol 70: 399-405, 2012. Ahn MJ, Kim DW, Kim TM, et al. Phase I study of AZD3759, a CNS penetrable EGFR inhibitor, for the treatment of non-small-cell lung cancer (NSCLC) with brain metastasis (BM) and leptomeningeal metastasis (LM)., ASCO Meeting Abstracts. 34 (2016) 9003. Goss G, Tsai CM, Shepherd F, et al. CNS Response to osimertinib in patients with T790M-positive advanced NSCLC: Pooled data from two phase II trials. J Thorac Oncol Vol. 12 No. 1S (MA16.11)x William J. Magnuson, Nataniel H. Lester-Coll, et al. Management of brain metastases in tyrosine kinase inhibitor–naïve epidermal growth factor receptor–mutant non–small-cell lung cancer: A retrospective multi-institutional analysis. J Clin Oncol 35:1070-1077.James Chih-Hsin Yang Welsh JW, Komaki R, Amini A, et al. Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer. J Clin Oncol 31: 895-902, 2013. Yu HA, Sima CS, Reales D, et al. A phase I study of twice weekly pulse dose and daily low dose erlotinib as initial treatment for patients (pts) with EGFR-mutant lung cancers. J Clin Oncol33(Suppl 15s): 426s, 2015. Yang J.C.-H, Kim DW, Kim, SW, et al. Osimertinib activity in patients (pts) with leptomeningeal (LM) disease from non-small cell lung cancer (NSCLC): Updated results from BLOOM, a phase I study., ASCO Meeting Abstracts. 34 (2016) 9002.Search for articles by this authorAffiliations Cancer Research Center, National Taiwan University, Taipei/Taiwan
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OA 03 - Mediastinal and Esophageal Tumor: Insight and New Treatment (ID 654)
- Event: WCLC 2017
- Type: Oral
- Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:M. Chida, Jhingook Kim
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 311 + 312
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OA 03.04 - A Phase II Study of Pembrolizumab for Patients with Refractory or Relapsed Thymic Epithelial Tumor (ID 9689)
11:30 - 11:40 | Author(s): Myung-Ju Ahn
- Abstract
- Presentation
Background:
No standard treatment exists for patients with thymic epithelial tumor (TET) who progress after platinum-containing chemotherapy. We conducted a phase II study of pembrolizumab in patients with refractory or relapsed TET to evaluate the efficacy and safety.
Method:
Between March 2016 and June 2017, patients with histologically confirmed TET who progressed after at least one platinum-containing chemotherapy were eligible. Patients were excluded if they had an active autoimmune disease requiring systemic treatment within the past one year or documented history of clinically severe autoimmune disease. Patients received 200mg of pembrolizumab intravenously every 3 weeks until tumor progression or unacceptable toxicity. Response was assessed every 9 weeks by investigator. The trial was registered with ClinicalTrials.gov, number NCT02607631.
Result:
Thirty-three patients were enrolled, 26 with thymic carcinoma and 7 with thymoma. 19 (57.3%) patients received two or more prior lines of systemic chemotherapy. Median number of cycles was 8 (ranges, 1-22) and median follow-up was 11.8 months (ranges, 1.6-14.9 months). Of 33 patients, eight (24.2%) achieved partial responses, 17 (51.5%) stable disease, and 8 (24.2%) progressive disease as best response, resulting in overall response rate of 24.2% (7 confirmed PR). The median progression-free survival was 6.1 months for both of thymoma and thymic carcinoma. The most common adverse events of any grade include dyspnea (11 [33.3%] of 33 patients), chest wall pain (10 [30.3%]), anorexia (7 [21.2%]) and fatigue (7 [21.2%]). Treatment-related adverse events ≥ grade 3 associated with immune related adverse events (irAE) include hepatitis (4 [12.1%]), myocarditis (3 [9.1%]), myasthenia gravis (2 [6.1%]), thyroiditis (1 [3.0%]), ANCA-associated rapidly progressive glomerulonephritis (1 [3.0%]), colitis (1 [3.0%]), and subacute myoclonus (1 [3.0%]) except anemia (1 [3.0%]). Eight (24.2%) patients (5 thymoma, 3 thymic carcinoma) discontinued study treatment due to irAE, whereas irAEs were manageable with immediate administration of high dose corticosteroid and other immunosuppressive agents in most of patients (7 of 8 [87.5%]). In 18 (54.5%) patients who had tumor specimens available for correlative biomarker analysis, all of four patients achieved partial response had 50% or more proportion score of PD-L1 immunostaining and higher PD-L1 RNA expression compared with non-responders (p=0.0471).
Conclusion:
Pembrolizumab showed promising antitumor activity in patients with refractory or relapsed TET. Given the relatively high incidence of irAEs especially in thymoma, early detection and management of autoimmune toxicity is essential to ensure feasibility of pembrolizumab treatment in patients with TET.
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OA 05 - Next Generation TKI (ID 657)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:James Chih-Hsin Yang, Fiona Blackhall
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 301 + 302
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OA 05.05 - Brigatinib in Crizotinib-Refractory ALK+ NSCLC: Updated Efficacy and Safety Results From ALTA, a Randomized Phase 2 Trial (ID 8027)
16:30 - 16:40 | Presenting Author(s): Myung-Ju Ahn
- Abstract
- Presentation
Background:
Brigatinib, a next-generation ALK inhibitor, recently received accelerated approval in the United States for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. We report updated data from the randomized phase 2 trial (ALTA; NCT02094573), which was designed to investigate the efficacy and safety of 2 brigatinib regimens in patients with crizotinib-refractory, advanced ALK+ NSCLC.
Method:
Patients were stratified by presence of brain metastases at baseline and best response to prior crizotinib and randomized 1:1 to receive brigatinib at 90 mg qd (arm A) or 180 mg qd with a 7-day lead-in at 90 mg (arm B). Investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1 was the primary endpoint.
Result:
Among 222 patients (n=112/n=110, arm A/B), median age was 51/57 years; 71%/67% had brain metastases. As of February 21, 2017, 17 full months since the last patient enrolled, median follow-up was 16.8/18.6 months and 32%/41% of patients continued to receive brigatinib in A/B. The table shows brigatinib efficacy. Per independent review committee, confirmed ORR was 51%/55% and median PFS was 9.2/16.7 months in A/B. Among patients with measurable baseline brain metastases (n=26/n=18, A/B), confirmed intracranial ORR was 50%/67% as of January 24, 2017; median intracranial DoR was not reached/16.6 months. The most common treatment-emergent adverse events (TEAEs) were: nausea (38%/47%, A/B), diarrhea (28%/44%), cough (28%/40%), headache (30%/35%), and vomiting (36%/30%); the most common grade ≥3 TEAEs were: increased creatine phosphokinase (5%/13%), hypertension (6%/8%), pneumonia (4%/5%), and increased lipase (5%/4%). Dose reduction (9%/30%, A/B) or discontinuation (4%/11%) due to TEAEs was reported.
Conclusion:
In ALTA, brigatinib continues to show substantial efficacy and acceptable safety at both dose levels, with numerically longer PFS and higher intracranial ORR at the recommended dosing regimen of 180 mg qd (with lead-in) vs 90 mg qd.Investigator Assessment Independent Review[a] Arm A (n=112) Arm B (n=110) Arm A (n=112) Arm B (n=110) Confirmed ORR, % 46 (35–57[b]) 55 (44–66[b]) 51 (41–61[c]) 55 (45–64[c]) Median DoR in responders,[d] months 12.0 (9.2–17.7[c]) 13.8 (10.2–17.5[c]) 13.8 (7.4–NR[c]) 14.8 (12.6–NR[c]) Median PFS,[d] months [% of events] 9.2 (7.4–11.1[c]) [65] 15.6 (11.1–19.4[c]) [50] 9.2 (7.4–12.8[c]) [54] 16.7 (11.6–NR[c]) [41] Median OS,[d] months [% of events] NR (20.2–NR[c]) [38] 27.6 (27.6–NR[c]) [29] — — 1-year OS probability,[d ]% 70 (61–78[c]) 80 (71–87[c]) — — DoR, duration of response NR, not reached OS, overall survival PFS, progression-free survival [a]Last scan date: February 28, 2017 [b]97.5% CI for primary endpoint [c]95% CI [d]Kaplan-Meier estimate
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OA 08 - Neuroendocrine Carcinoma: Translational (ID 667)
- Event: WCLC 2017
- Type: Oral
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:David S Ettinger, S. Zöchbauer-Müller
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 311 + 312
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OA 08.07 - Pazopanib Maintenance for Extensive Disease Small Cell Lung Cancer: a Randomized, Placebo-Controlled Phase II study (KCSG-LU12-07) (ID 8239)
12:05 - 12:15 | Author(s): Myung-Ju Ahn
- Abstract
- Presentation
Background:
We investigated whether pazopanib maintenance following first-line chemotherapy would improve survival in patients with extensive disease small-cell lung cancer (ED-SCLD).
Method:
This study is a randomized, placebo-controlled, phase II study that enrolled ED-SCLC patients who had not progressed after four cycles of etoposide plus platinum combination therapy. Eligible patients were randomly assigned (1:1 ratio) to either placebo or pazopanib 800 mg per day until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS).
Result:
Ninety-seven patients were enrolled and randomly assigned; 2 patients did not receive study drugs. In total, 95 patients received maintenance therapy (pazopanib, n = 48; placebo, n = 47) and were included into the analyses. Grade 3 toxicities for pazopanib maintenance included thrombocytopenia (10.4%, including 1 case with grade 4 toxicity), liver enzyme elevation (10.4%), fatigue (6.3%), and hypertension (6.3%). Median PFS was 3.7 months for pazopanib maintenance and 1.8 months for placebo (Hazard ratio [HR] 0.44, 95% CI: 0.29 – 0.69, p < 0.0001). Median PFS longer than 6 months were achieved by 9 patients (18.8%) in pazopanib arm and 2 (4.3%) in placebo. Median overall survival for the pazopanib and placebo arms were 10.6 months and 12.9 months, respectively (HR 1.14, 95% CI: 0.74 – 1.76, p = 0.54).
Conclusion:
Though this study met the primary endpoint of PFS, it failed to translate into improvement of overall survival with pazopanib maintenance. Given the unneglectable toxicity profiles, relevant biomarkers to select patients for benefit from pazopanib should be further investigated.
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OA 09 - EGFR TKI Resistance (ID 663)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Thanyanan Reungwetwattana, Lecia V Sequist
- Coordinates: 10/17/2017, 11:00 - 12:30, Room 301 + 302
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OA 09.03 - TATTON Ph Ib Expansion Cohort: Osimertinib plus Savolitinib for Pts with EGFR-Mutant MET-Amplified NSCLC after Progression on Prior EGFR-TKI (ID 8985)
11:20 - 11:30 | Presenting Author(s): Myung-Ju Ahn
- Abstract
- Presentation
Background:
MET amplification is a well described mechanism of acquired resistance to EGFR inhibition in EGFR-mutant NSCLC, making combined MET/EGFR inhibition a compelling therapeutic approach. We previously reported tolerability of the oral, CNS active, third-generation EGFR-TKI osimertinib, which is selective for both EGFR-TKI sensitizing and EGFR T790M resistance mutations, combined with the highly selective MET-TKI savolitinib (volitinib, HMPL-504, AZD6094). Here we assess safety and preliminary activity of this combination in a cohort of patients (pts) with EGFR-mutant NSCLC and MET-positive acquired resistance in the multi-arm, Phase Ib TATTON study (NCT02143466).
Method:
Eligible pts were aged ≥18 years (WHO performance status 0/1) with locally advanced or metastatic EGFR-mutant NSCLC who progressed on at least one prior EGFR-TKI with centrally confirmed MET-amplification (fluorescence in-situ hybridisation, MET gene copy ≥5 or MET/CEP7 ratio ≥2). Pts received osimertinib 80 mg QD plus savolitinib 600 mg QD. Primary objective was safety and tolerability; secondary objectives included preliminary assessment of anti-tumour activity and pharmacokinetics.
Result:
As of data-cut off (15 April 2017), 45 pts with centrally confirmed MET-amplification (FISH) were enrolled and received treatment, including 25 pts previously treated with a third-generation EGFR-TKI and 20 without prior third-generation EGFR-TKI treatment (T790M negative n=13; T790M positive n=7). At baseline, median age was 58 years (range 38–76), 24 (53%) were female, 36 (80%) were Asian. The most frequent adverse events (AEs) were nausea (n=21, 47%), decreased appetite (n=15, 33%), fatigue (n=13, 29%) vomiting (n=13, 29%), rash (n=11, 24%), myalgia (n=8, 18%), pyrexia (n=7, 16%), ALT/AST increased (n=6, 13%), and WBC decreased (n=6, 13%), consistent with the known safety profiles. Serious AEs were reported in 15 (33%) pts; events reported in >1 patient were pneumonia, dyspnoea, acute kidney injury and pyrexia (all n=2). Four pts died due to AEs, none were considered related to study drugs. At data cut-off, confirmed partial responses were reported in 5/25 (20%) pts previously treated with a third-generation EGFR-TKI; 5/12 (42%) T790M negative pts without prior third-generation EGFR-TKI and 3/7 (43%) T790M positive pts without prior third-generation EGFR‑TKI. Twenty-eight (62%) pts are ongoing treatment. Preliminary steady-state exposures and pharmacokinetic parameters of savolitinib and osimertinib were consistent with historical data.
Conclusion:
These findings demonstrate promising safety, tolerability, and preliminary activity of osimertinib plus savolitinib and support further investigation of this combination for the treatment of pts with locally advanced or metastatic EGFR-mutant NSCLC and MET-amplification. Updated data will be presented.
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OA 10 - Liquid Biopsy for Genomic Alterations (ID 678)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Adrian G. Sacher, Pasi A Jänne
- Coordinates: 10/18/2017, 11:00 - 12:30, F201 + F202 (Annex Hall)
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OA 10.01 - Detection of EGFR mutations from plasma ctDNA in the osimertinib Phase III trial (AURA3): comparison of three plasma assays (ID 8984)
11:00 - 11:10 | Presenting Author(s): Myung-Ju Ahn
- Abstract
- Presentation
Background:
AURA3 (NCT02151981) showed osimertinib, a third-generation EGFR-TKI, significantly prolongs progression‑free survival and improves response rate vs platinum‑pemetrexed in patients with T790M-positive advanced NSCLC, whose tumors had progressed on first-line EGFR-TKI therapy. Using patient baseline samples, we report concordance between plasma circulating tumor DNA (ctDNA) and tissue for the detection of EGFR mutations (T790M, exon 19 deletions [Ex19Del], L858R) using three distinct plasma detection technologies.
Method:
Tumor tissue biopsy samples were taken following progression on first-line EGFR‑TKI treatment. Baseline central confirmation of EGFR mutation status was by cobas[®] EGFR Mutation Test (Roche Molecular Systems). Where possible, baseline blood samples for plasma ctDNA screening were collected from patients in the osimertinib treatment group and analyzed using allele specific (AS)‑PCR (cobas[®] EGFR Mutation Test v2), ddPCR (Biodesix) and next generation sequencing (NGS, Guardant Health).
Result:
Figure 1 ctDNA was undetectable (negative for all three EGFR mutations [T790M, Ex19Del, L858R]) in 51/228 (22%) patients by AS-PCR, 58/211 (27%) by ddPCR, and 54/230 (23%) by NGS. Robust correlations (Spearman’s Rank) were observed for EGFR mutant allelic fractions (AFs) between ddPCR and NGS assays: T790M R[2] 0.9129 (n=201), Ex19Del R[2] 0.9384 (n=201), L858R R[2] 0.8090 (n=200). Discordant results between ddPCR and NGS were observed in 24/201 (12%) samples for T790M, 17/201 (8%) Ex19Del and 11/200 (6%) L858R. All discordant samples had AFs ≤1% by both assays.
Conclusion:
Using cobas tissue test as a reference, sensitivity for the detection of plasma T790M appeared higher for ddPCR and NGS assays compared with AS-PCR. Robust correlations were observed between quantitative ddPCR and NGS assays for determination of AFs across all three mutations. About 25% of AURA3 patients did not appear to shed ctDNA, as evidenced by absence of all three EGFR mutations across the three platforms.
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OA 14 - New Paradigms in Clinical Trials (ID 681)
- Event: WCLC 2017
- Type: Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Alex Adjei, Eun Kyung Cho
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 311 + 312
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OA 14.06 - Entrectinib in Patients with Locally Advanced or Metastatic ROS1 Fusion-Positive Non-Small Cell Lung Cancer (NSCLC) (ID 8564)
11:55 - 12:05 | Presenting Author(s): Myung-Ju Ahn
- Abstract
- Presentation
Background:
Entrectinib is a potent, investigational, CNS-active, oral inhibitor of ROS1 with a biochemical IC~50~ (0.2 nM) ~30 times more potent than crizotinib, the only agent approved for the treatment of ROS1-positive NSCLC. Previously, we reported an objective response rate of 85% in 13 ROS1 inhibitor-naïve NSCLC patients who were treated in Phase 1 studies (Drilon and Siena et al, Cancer Discov 2017), including 2 of 3 (67%) patients with CNS disease. Responses were durable, with 1 patient remaining on study for more than 3 years. Entrectinib was well tolerated, with predominantly Grades 1 or 2 adverse events that were reversible with dose modification.
Method:
Patients with ROS1 inhibitor-naïve NSCLC were enrolled across Phase 1 and 2 studies of entrectinib. Patients were screened for ROS1 gene fusions either locally or centrally at Ignyta’s diagnostic laboratory using next generation sequencing. Entrectinib was administered orally at 600 mg once-daily in 4-week cycles. Safety was assessed by monitoring adverse events, laboratory tests, and clinic visits. Tumor assessments were performed at the end of Cycle 1 and every 8 weeks thereafter. All scans were read locally (INV) and by blinded independent central review (BICR) using RECIST v1.1. INV results will be presented except where noted.
Result:
As of 24 May 2017, a total of 32 patients were evaluable for response (median age 52 years, 72% female). At a median follow-up of 12 months, objective responses were observed in 24 of 32 (75% [95% CI: 56.6, 88.5]; 3 complete responses) patients, including 7 of 11 (64% [95% CI: 30.8, 89.1]) patients with CNS disease at baseline. Five of 7 patients with evaluable CNS lesions by BICR experienced confirmed RECIST intracranial responses, for a CNS response rate of 71% (95% CI: 29.0, 96.3). With 19 (59%) patients remaining on study, the median duration of response was 17.2 months (95% CI: 6.5, 36.0) and progression-free survival was 19.1 months (95% CI: 6.5, 36.6). The most common (>15%) treatment-related adverse events were fatigue/asthenia (34%), dysgeusia (34%), dizziness (24%), weight increase (21%), paresthesia (19%), nausea (18%), constipation (18%), and diarrhea (16%). All data will be updated at the time of presentation.
Conclusion:
Entrectinib is well tolerated and has shown promising antitumor activity in ROS1 inhibitor-naïve NSCLC, including patients with CNS disease. Patients with ROS1+ NSCLC and other tumor types continue to be enrolled in STARTRK-2 (NCT02568267) in order to support a potential regulatory filing for entrectinib in this population.
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-001 - Depth of Target Lesion Response to Brigatinib and Its Association With Outcomes in Patients With ALK+ NSCLC in the ALTA Trial (ID 8035)
09:30 - 09:30 | Author(s): Myung-Ju Ahn
- Abstract
Background:
Depth of target lesion response to crizotinib has been associated with overall survival (OS) (J Clin Oncol 2016;34:abstract 2590). ALTA (NCT02094573) is an ongoing randomized phase 2 trial of brigatinib, an ALK inhibitor, in crizotinib-refractory advanced ALK+ NSCLC patients. As the ALTA primary endpoint of confirmed objective response rate (cORR), a binary outcome, might not fully capture clinical benefit, we examined the association of maximum decrease in target lesions with progression-free survival (PFS) and OS.
Method:
Patients were randomized to receive brigatinib at 90 mg qd (arm A; n=112) or 180 mg qd with a 7-day lead-in at 90 mg (arm B; n=110). Arms were pooled in this analysis. Patients with any target lesion shrinkage were sorted into 4 groups based on greatest decrease from baseline per RECIST v1.1; outcomes in these groups were compared with outcomes in patients with no shrinkage.
Result:
As of February 21, 2017, cORR in arm A/B (ITT population) was 46%/55% per investigators. 201/222 patients had ≥1 evaluable response assessment with 18.4-month median follow-up. Median age of these patients was 53 years; 57% were female. Patients with target lesion shrinkage (vs none) had numerically longer PFS (hazard ratios [95% CIs]: 0.61 [0.30–1.22], 1%–25% shrinkage; 0.47 [0.24–0.91], 26%–50%; 0.54 [0.28–1.05], 51%–75%; 0.30 [0.15–0.63], 76%–100%) and numerically higher estimated 1-year OS (Table). In a multivariable analysis, 76%–100% shrinkage (vs none) was independently associated with longer PFS/OS (hazard ratios [95% CIs]: 0.37 [0.18–0.76]/0.35 [0.14–0.89]); arm B (vs A) was independently associated with longer PFS.
Conclusion:
In this exploratory post hoc analysis, brigatinib-treated patients with target lesion shrinkage, including those without confirmed partial response, had improved PFS/OS vs patients without shrinkage. Patients with the deepest response (76%–100% shrinkage) appeared to have the longest PFS and higher estimated 1-year OS.Best Target Lesion Shrinkage n (%)[a] Median PFS,[b,c] Months (95% CI) Median OS,[b ]Months (95% CI) 1-year OS,[b ]% (95% CI) None 18 (9) 3.7 (1.9–11.0) 8.3 (4.7–NR) 48 (22–99) 1%–25% 40 (20) 9.3 (4.0–21.2) NR (14.5–NR) 75 (58–99) 26%–50% 60 (30) 12.8 (9.2–15.7) NR (NR–NR) 82 (70–99) 51%–75% 44 (22) 11.1 (7.4–18.2) 27.6 (20.2–NR) 77 (62–99) 76%–100% 39 (19) 19.5 (12.6–NR) NR (22.3–NR) 92 (78–99) NR, not reached [a]Evaluable patients [b]Kaplan-Meier estimate [c]Per investigator
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P1.01-004 - Hypertension With Brigatinib: Experience in ALTA, a Randomized Phase 2 Trial in Crizotinib-Refractory ALK+ NSCLC (ID 8346)
09:30 - 09:30 | Author(s): Myung-Ju Ahn
- Abstract
Background:
The next-generation ALK inhibitor brigatinib received accelerated approval in the United States in April 2017 for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. Hypertension has been identified as an adverse event of interest with brigatinib treatment based on prior clinical data; here, we report incidence, management, and outcomes of hypertension in ALTA (NCT02094573).
Method:
In ALTA, 222 patients were randomized 1:1 to receive brigatinib at 90 mg qd (arm A; n=112 randomized, n=109 treated) or 180 mg qd with a 7-day lead-in at 90 mg (arm B; n=110 randomized and treated). A medical history of hypertension was allowed, but patients with significant, uncontrolled, or active cardiovascular disease were excluded. Blood pressure (BP) was measured at screening, on days 1, 8, and 15 of the first 28-day cycle, and then every 4 weeks (starting on day 1 of cycle 2).
Result:
Median age was 50/57 years in treated patients in A/B; 22%/25% of treated patients in A/B had a history of hypertension at baseline. As of February 21, 2017, hypertension was reported as a treatment-emergent adverse event (TEAE; any grade) in 17%/27% of patients (A/B) and as a grade 3 TEAE in 6%/8%; no grade 4 hypertension was reported. Few patients had dose interruptions (1%/2%, A/B) or reductions (1%/1%) due to hypertension; no patients discontinued brigatinib due to hypertension. Among patients with hypertension, median time to onset of first hypertension TEAE was 5.8 months/2.1 months in A/B. Among patients with baseline systolic BP <120 mmHg (n=50/n=48, A/B), 20%/42% had a maximum shift to 140–159 mmHg postbaseline (6%/10%, <120 mmHg to ≥160 mmHg); among patients with baseline diastolic BP <80 mmHg (n=68/n=72, A/B), 29%/35% had a maximum shift to 90–99 mmHg postbaseline (10%/8%, <80 mmHg to ≥100 mmHg). Among patients with hypertension TEAEs (n=19/n=30, A/B), 84%/80% started a new antihypertensive medication during the study. Among patients with hypertension TEAEs and no medical history of hypertension (n=11/n=20, A/B), 73%/70% started a new antihypertensive medication during the study. Cardiovascular events in patients with hypertension TEAEs included: angina pectoris in 1 patient without a medical history of hypertension and, in patients with a medical history of hypertension, hypertensive retinopathy (n=1), intermittent claudication (n=1), and peripheral artery stenosis (n=1).
Conclusion:
Hypertension was observed frequently with brigatinib, and appeared dose-related, but was managed with antihypertensive therapy and rarely led to dose modification or discontinuation.
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P1.08 - Locally Advanced NSCLC (ID 694)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.08-004 - Adjuvant Chemoradiotherapy vs. Chemotherapy for Completely Resected Unsuspected N2-Positive Non-Small Cell Lung Cancer (ID 8238)
09:30 - 09:30 | Author(s): Myung-Ju Ahn
- Abstract
Background:
We investigated whether concurrent chemoradiotherapy (CCRT) would increase survival in patients with completely resected unsuspected N2-positive non-small cell lung cancer (NSCLC), compared with adjuvant chemotherapy alone.
Method:
Eligible patients were randomly assigned (1:1 ratio) to either the CCRT arm or the chemotherapy arm. In the CCRT arm, patients received concurrent thoracic radiotherapy (50 Gy in 25 fractions) with five cycles of weekly paclitaxel (50 mg/m[2]) and cisplatin (25 mg/m[2]), followed by two additional cycles of paclitaxel (175 mg/m[2]) plus cisplatin (80 mg/m[2]) at three-week intervals. In the chemotherapy arm, patients received four cycles of adjuvant paclitaxel (175 mg/m[2]) and carboplatin (AUC 5.5) every three weeks. The primary endpoint was disease-free survival.
Result:
We enrolled and analyzed 101 patients. The median disease-free survival of the CCRT arm was 24.7 months, which was not significantly different from that of the chemotherapy arm (21.9 months; hazard ratio [HR] 0.94, 95% CI: 0.58–1.52, P = 0.40). There was no difference in overall survival (CCRT: 74.3 months, chemotherapy: 83.5 months, HR: 1.33, 95% CI: 0.71–2.49). Subgroup analysis showed chemotherapy alone increased overall survival in never-smokers and multi-station N2-positive patients. The pattern of disease recurrence was similar between the two arms.
Conclusion:
There was no survival benefit from adjuvant CCRT compared with platinum-based chemotherapy alone for completely resected unsuspected N2-positive NSCLC.
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P2.01 - Advanced NSCLC (ID 618)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:00 - 16:00, Exhibit Hall (Hall B + C)
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P2.01-064 - Co-Existing Mutations and Their Clinical Implications in Non-Small Cell Lung Cancer: Korean Lung Cancer Consortium (KLCC-13-01) (ID 8838)
09:00 - 09:00 | Author(s): Myung-Ju Ahn
- Abstract
Background:
Non-small cell lung cancer (NSCLC) is a common type of cancer with typically poor prognosis. As individual cancers exhibit unique mutation patterns, identifying and characterizing gene mutations in NSCLC might help predict patient outcomes and guide treatment. The aim of this study was to characterize the mutational landscape of NSCLC and identify biomarkers to predict patient outcome.
Method:
Archived DNA was extracted from formalin-fixed, paraffin-embedded, mostly small biopsy samples of 162 patients. Targeted sequencing of genomic alterations was conducted using Ion AmpliSeq Cancer Hotspot Panel v2.
Result:
The median age of patients was 64 years (range; 32-83 years) and the majority had stage IV NSCLC at the time of cancer diagnosis (90%). Among the 162 patients, 161 patients (99.4%) had novel or hotspot mutations (range: 1-16 mutated genes). Hotspot mutations were found in 20 genes. Three of the most frequently found hotspot mutations were in TP53 (82, 51.2%), EGFR (66, 40.8%), and STK11 (19, 11.7%). Given that 72.7% (48/66) of EGFR mutant patients were treated with EGFR TKIs, there was a significant difference in overall survival between EGFR mutant and EGFR wild-type patients. In EGFR wild-type subgroup analysis, TP53 status was associated with poor overall survival, while STK11 status was associated both poor progression-free survival and overall survival.
Conclusion:
These results suggest that targeted next-generation sequencing using small biopsy samples is feasible and allows for the detection of both common and rare mutations that have independent prognostic value.
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P2.07 - Immunology and Immunotherapy (ID 708)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.07-025 - Increased Antitumor Response to Chemotherapy Administered after PD-1/PD-L1 Inhibitors in Patients with Non-Small Cell Lung Cancer (ID 8707)
09:30 - 09:30 | Author(s): Myung-Ju Ahn
- Abstract
Background:
The role of anti-PD-1/PD-L1 inhibitor monotheapy has been demonstrated for advanced non-small cell lung cancer (NSCLC). However, its benefits in terms of response and progression-free survival are limited to small proportion of patients. The successful treatment of advanced NSCLC requires a combination of various treatment modalities. Therefore, this study evaluated whether subsequent chemotherapy administered after immunotherapy (PD-1/PD-L1 inhibitors) (SCAI) would have enhanced antitumor response in patients with NSCLC.
Method:
This study included patients with available response data for their SCAI. We compared the objective response rates of SCIA with those of the last chemotherapy administered before immunotherapy (LCBI).
Result:
In total, 73 patients met the inclusion criteria and were included into the analyses. Among them, 10 patients received PD-1/PD-L1 inhibitors as first-line therapy, and therefore 63 had available response data for LCBI. The ORR of SCAI and LCBI were 53.4% and 34.9%, respectively (P = 0.03). Out of 73 SCAI, 24 were platinum-doublet chemotherapy and 49 were non-platinum monotherapy, and among 63 LCBI, 43 and 20 were platinum-doublet and non-platinum monotherapy, respectively. The ORR for platinum-doublet of SCAI and LCBI were 66.7% (16/24) and 39.5% (17/43), respectively (p = 0.03). The ORR for non-platinum of SCAI and LCBI were 46.9% (23/49) and 25.0% (5/20), respectively (p = 0.09). Figure 1
Conclusion:
The ORR for SCAI was significantly higher than that of LCBI. This data indicate anti-PD-1/PD-L1 inhibitors could make tumors more vulnerable to subsequent chemotherapy.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 3
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-023 - First-line Afatinib for Non-Small Cell Lung Cancer in Real World Practice (ID 8947)
09:30 - 09:30 | Author(s): Myung-Ju Ahn
- Abstract
Background:
The efficacy of first-line afatinib was demonstrated for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) in large randomized trials, and it has been approved and reimbursed in South Korea since year 2014. This study evaluated clinical outcomes of afatinib in real world practice.
Method:
Patients treated with first-line afatinib for advanced EGFR-mutant NSCLC in Samsung Medical Center (Seoul, South Korea) from October 2014 to December 2016 were included into the analyses.
Result:
In total, 165 patients were analyzed. One hundred fourteen had deletion in exon 19, 37 L858R, and 14 patients had uncommon EGFR mutations including 4 de novo T790M. Median progression-free survival (PFS) was 19. 1 months (95% CI: 12.3- 25.9 months). There was difference in median PFS according to EGFR mutation type: deletion in exon 19 (19.1 months), L858R (15.8 months), de novo T790M (4.7 months), and uncommon EGFR excepting for T790M (not yet reached) (P = 0.01). Though 112 patients (67.8%) had to reduce afatinib dose from 40 mg per day into 30 mg or 20 mg per day due to adverse events, it did not impair its efficacy in terms of PFS (23.5 months in a reduction group vs. 12.4 months in no reduction group). Among 29 patients with evaluable follow-up brain MRI for non-irradiated brain metastatic lesions, significant response was documented in 22 cases (75.9%). Out of 20 patients who were biopsied again at disease progression (excluding one case with de novo T790M), T790M appeared in 7 the repeat-biopsied specimens (35.0%).
Conclusion:
In the real practice in South Korea, first-line afatinib showed comparable or better efficacy data compared with previous clinical trials.
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P3.01-029 - Transient Asymptomatic Pulmonary Opacities (TAPOs) during Osimertinib Treatment and Its Clinical Implication (ID 9117)
09:30 - 09:30 | Author(s): Myung-Ju Ahn
- Abstract
Background:
Osimertinib is an oral, potent, irreversible 3[rd] generation EGFR tyrosine kinase inhibitor(TKI) approved for the treatment of T790M positive non-small cell lung cancer (NSCLC) patients who failed 1[st] or 2[nd] generation EGFR TKIs. Interstitial lung disease (ILD) is a rare complication with osimertinib, accounting for 1-3%. Recently, relatively high incidence of transient asymptomatic pulmonary opacities (TAPOs) which are different from ILD has been described (Noonan et al, JTO 2016). However, its clinical implication has not been fully determined yet.
Method:
We retrospectively analyzed 75 EGFR mutant NSCLC patients treated with osimertinib at Samsung Medical Center. Serial CT findings were reviewed by radiologist (Dr. HY Lee) and TAPO was classified according to its radiologic pattern. We also analyzed the correlation of TAPO with clinical outcomes.
Result:
Among 74 patients, TAPO was found in 15 (20.3%). The median time to TAPOs development was 23.5 weeks (1 – 72 weeks) and the median duration of TAPOs was 6.0 weeks (5 – 24 weeks) during continued osimertinib treatment. The most common radiological patterns of TAPO include cryptogenic organizing pneumonia and/or simple eosinophilic pneumonia (SEP). There was no significant difference in patient characteristics between TAPO positive and negative group. The duration of exposure to osimertinib is longer in TAPO positive than negative group (25.2 months vs 14.0 months, p=0.016 ). The progression free survival (PFS) and overall survival (OS) was numerically longer in patients with TAPO positive than negative group (PFS : 15.0 m vs 12.5 m, p= 0.201/ OS : 37.0 m vs 24 m, p=0.155)
Conclusion:
TAPOs are frequently observed with osimertinib treatment and may be mistaken for isolated pulmonary progression or ILD. Given the lack of serious clinical deterioration, it is reasonable to continue osimertinib with regular CT scan follow-up. For further clinical validation of TAPOs, long-term and large studies are warranted.
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P3.01-082 - Surgical Rebiopsy in Advanced Non-Small Cell Lung Cancer Resistant to Previous Chemotherapy (ID 10505)
09:30 - 09:30 | Author(s): Myung-Ju Ahn
- Abstract
Background:
To optimize the personalized medicine for advanced non-small cell lung cancer (NSCLC), sufficient tumor tissue is mandatory to analyze molecular and genetic profile. The demand for repeat biopsy in NSCLC is increasing, it is more difficult to obtain specimen after initial treatment. The aim of this study was to evaluate the impact of surgical rebiopsy in advanced NSCLC.
Method:
From Jan 2014 to Mar 2017, 146 consecutive patients underwent surgical rebiopsy for NSCLC which was resistant to prior chemotherapy. Their medical record were reviewed retrospectively.
Result:
There were 60 male and 86 female patients with mean age of 57 years (range 30-83). Adenocarcinoma was most common histologic type (n=142, 93%). Among them, 107 patients represent EGFR mutation before chemotherapy, deletion in exon 19 (n=73) was most frequently observed. Before surgical rebiopsy, 121 patients (83%) were treated with EGFR-TKIs. The mean number of change in chemotherapy regimen was 2 (range 1-6) and 24% of patients underwent more than 3 different chemotherapy before rebiopsy. The median time between initial treatment and rebiopsy was 17.4 months (IQR 9-25). Surgical rebiopsy was possible in all cases. One hundred and seven patients (73%) underwent pleura biopsy, 22 underwent lung resection and 12 patients underwent both pleural and lung resection. Most procedure underwent video-assisted thoracic surgery (n=136, 93%), 10 patients required mini-thoracotomy. Median postoperative hospital stay was 4 days (IQR, 3-6) and the 30-day mortality was 2.7%. All specimens were confirmed as NSCLC and adequate for mutational and genetic analysis except 2 patients. One patient was failed to mutational analysis, other patients was failed to genetic sequencing due to low tumor volume. After surgery, 129 patients can resume chemotherapy. Of those, 85 patients were enrolled clinical trial or treated with new target agent. Thirty nine patients were treated with cytotoxic chemotherapy and 5 patients continued with prior target agent.
Conclusion:
Surgical rebiopsy can detect changes in cancer characteristics and may be used in therapeutic decision making in advanced NSCLC resistant to previous treatment.
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P3.03 - Chemotherapy/Targeted Therapy (ID 719)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.03-012 - The Relationship between Efficacy of Wee1 Inhibitor AZD1775 and Mutational Status of TP53 in KRAS-Mutant Non-Small Cell Lung Cancer (ID 8844)
09:30 - 09:30 | Author(s): Myung-Ju Ahn
- Abstract
Background:
KRAS is frequently mutated in non-small cell lung cancer (NSCLC). However, direct targeting of KRAS has proven to be challenging, and inhibition of KRAS effectors has resulted in limited clinical efficacy. Wee1 kinase is an important regulator of the G2 checkpoint and is overexpressed in various cancers. Inhibition of Wee1 exerts anticancer effects as a monotherapy or in combination with DNA-damaging agents when cancer cells harbor TP53 mutations. However, its role in KRAS-mutant NSCLC, especially as a single agent, has not been explored.
Method:
Here, we investigate the anticancer potential of Wee1 inhibitor AZD1775 as a monotherapy and uncover a possible cellular context underlying sensitivity to AZD1775. Eight KRAS-mutant NSCLC cell lines were treated with AZD1775 and cell viability, proliferation, and cell cycle were analyzed. Target modulation was assessed by Western blotting and immunohistochemistry.
Result:
Our data show that treatment with AZD1775 significantly inhibited cell survival, growth, and proliferation of TP53-mutant (TP53[MUT]) compared to TP53 wild-type (TP53[WT]) in KRAS-mutant (KRAS[MUT]) NSCLC cells. In KRAS[MUT]/TP53[MUT] cells, AZD1775 treatment led to DNA damage, a decrease of survival signaling, and cell death by apoptosis. Interestingly, cell death through apoptosis was found to be heavily dependent on specific cellular genetic context, rather than inhibition of Wee1 kinase activity alone. In addition, AZD1775 treatment was well tolerated and displayed single-agent efficacy in a mouse xenograft model.
Conclusion:
This study provides rationale for inhibiting Wee1 using AZD1775 as a potential anticancer therapy against the TP53[MUT] subgroup of KRAS[MUT] NSCLC.
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P3.08 - Locally Advanced Nsclc (ID 724)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.08-006 - Treatment Response and Survival Outcomes Are Associated with Histologic Type in Non-Small Cell Lung Cancer Treated with Trimodal Treatment (ID 9972)
09:30 - 09:30 | Author(s): Myung-Ju Ahn
- Abstract
Background:
Trimodal treatment incorporating neoadjuvant concurrent chemoradiotherapy (CCRT) and surgical resection is one of the treatment strategies for non-small cell lung cancer (NSCLC) patients with N2 disease. Although pathologic phenotypes as well as biological features might be different between adenocarcinoma (ADC) and squamous cell carcinoma (SqCC), histologic type has been rarely considered when selecting treatment strategy in patients with N2 disease. The aim of this study is to investigate if histologic type is associated with treatment response and survival outcomes in patients undergoing trimodal treatment for N2 disease.
Method:
A retrospective review of patients with N2 disease who underwent neoadjuvant CCRT followed by surgery at our institution was performed. Clinicopathologic features, response to CCRT, and survival outcomes were compared between ADC and SqCC.
Result:
From 2003 to 2013, 374 patients underwent curative-intent surgery after neoadjuvant CCRT for either ADC (n=233, 62.3%) or SqCC (n=141, 37.7%) with pathologically proven N2 disease. Sixty-nine patients (18.5%) had bulky and/or multi-stationed N2 diseases on pre-CCRT imaging tests. There were more male, more smokers, more advanced clinical T and N stages, and more bulky and/or multi-stationed N2 diseases in the SqCC group than in the ADC group. Conversely, the SqCC group had more radiologic responders, earlier pathologic T and N stages, more pathologic complete responders, and more frequent mediastinal downstaging than the ADC group. With a mean follow-up of 50.1 months, patients with SqCC showed significantly better 5-year recurrence-free survival than those with ADC (ADC, 22.8% vs. SqCC, 43%; p=0.001). However, there was no significant difference in the 5-year overall survival between the two groups (ADC, 57.5% vs. SqCC, 52.3%; p=0.366). This may be related to significantly better (p<0.001) post-recurrence survival in the ADC group (mean, 28 months) than in the SqCC group (mean, 14.5 months). In the ADC group, 164 patients developed recurrences and of those, 68 (41.5%) received targeted therapy. Patients who received targeted therapy for recurrences showed significant better 5-year overall survival than those who did not receive (61% vs. 45.6%, p=0.025).
Conclusion:
In this study, SqCC was associated with better treatment response and more favorable recurrence-free survival than ADC. Despite poor recurrence-free survival in ADC, its overall survival was improved by prolonged post-recurrence survival, which might be related to the use of targeted therapy for recurrence. Since treatment response and survival outcomes are different according to histologic type, individualized treatment strategy could be considered to improve outcomes of N2 disease.
