Liquid Biopsy Testing Can Improve Selection of Advanced Non-Small-Cell Lung Cancer Patients to Rechallenge With Gefitinib

The ICARUS trial is a phase II, open label, multicenter, single arm study conducted to investigate the efficacy, safety, and tolerability of a rechallenge treatment with the first-generation tyrosine kinase inhibitor (TKI) gefitinib in advanced non-small-cell lung cancer (NSCLC) patients carrying activating mutations of the epidermal growth factor receptor (EGFR). The ICARUS trial enrolled 61 patients who were rechallenged with gefitinib at progression after second-line chemotherapy. Serum-derived circulating cell-free DNA (cfDNA) collected before the rechallenge from a cohort of 29 patients, was retrospectively analyzed for the EGFR exon 19 deletions and for the p.L858R and p.T790M single nucleotide variants (SNV). The analysis of cfDNA detected the same EGFR activating mutation reported in the tumor tissue in 20/29 patients, with a sensitivity of 69%. Moreover, a p.T790M variant was found in 14/29 patients (48.3%). The median progression-free survival (PFS) was 2.7 months for p.T790M positive patients (CI 95% 1.4–3.1 months) versus 3.5 months for the p.T790M negative patients (CI 95% 1.6–5.3 months), resulting in a statistically significant difference (Long rank test p = 0.0180). These findings confirmed the role of the p.T790M mutation in the resistance to first-generation TKIs. More importantly, our data suggest that TKI rechallenge should be guided by biomarker testing.

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Randomized Phase II Study of Docetaxel plus Personalized Peptide Vaccination versus Docetaxel plus Placebo for Patients with Previously Treated Advanced Wild Type EGFR Non-Small-Cell Lung Cancer

Journal of Immunology Research ◽

10.1155/2016/1745108 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 8

Author(s):

Koichi Takayama ◽

Shunichi Sugawara ◽

Yasuo Saijo ◽

Makoto Maemondo ◽

Atsushi Sato ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Clinical Investigation ◽

Small Cell ◽

Rank Test ◽

Peptide Vaccination ◽

Small Cell Lung ◽

Significant Difference ◽

Previously Treated

Objectives. To evaluate the efficacy and safety of personalized peptide vaccination (PPV) combined with chemotherapy for patients with previously treated advanced non-small-cell lung cancer (NSCLC).Patients and Methods. Previously treated PS0-1 patients with IIIB/IV EGFR (epidermal growth factor receptor) wild genotype NSCLC were randomly assigned to docetaxel (60 mg/m2on Day 1) plus PPV based on preexisting host immunity or docetaxel plus placebo. Docetaxel administration was repeated every 3 weeks until disease progression. Personalized peptides or placebo was injected subcutaneously weekly in the first 8 weeks and biweekly in subsequent 16 weeks. The primary efficacy endpoint was progression-free survival (PFS).Results. PPV related toxicity was grade 2 or less skin reaction. The median PFS for placebo arm and PPV arm was 52 days and 59 days, respectively. There was no significant difference between two arms by log-rank test (p=0.42). Interestingly, PFS and overall survival (OS) in humoral immunological responder were significantly longer than those in nonresponder.Conclusion. PPV did not improve the survival in combination with docetaxel for previously treated advanced NSCLC. However, PPV may be efficacious for the humoral immunological responders and a further clinical investigation is needed.

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Comparison of efficiency and toxicity of two chemotherapy protocols in treatment of advanced non-small cell lung cancer

Medicinski pregled ◽

10.2298/mpns1108368m ◽

2011 ◽

Vol 64 (7-8) ◽

pp. 368-372 ◽

Cited By ~ 3

Author(s):

Alma Mekic-Abazovic ◽

Ibrahim Sisic ◽

Vladimir Kovcin ◽

Hakija Beculic ◽

Senad Dervisevic ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Tumour Response ◽

Progression Free Survival ◽

Small Cell ◽

Rank Test ◽

Small Cell Lung ◽

Free Survival ◽

Significant Difference

Introduction. This study was aimed at comparing the efficiency and tolerability of two reference protocols Cisplatin and Etoposide and Cisplatin and Vinorelbine in advanced Non-Small Cell Lung Cancer. Material and Methods. A total of 60 patients (two groups consisting of 30 patients) were treated for advanced Non-Small Cell Lung Cancer during the period from January to December 2005 according to the reference protocols (Cisplatin 100mg/m2 D1; Vinorelbine 30 mg/m2 D1, D8 on 4 weeks) and (Cisplatin 100 mg/m2 D1; Etoposide 100 mg/m2 D1, D3, D5 on 4 weeks) at the Department of Oncology of KBC ?Bezanijska kosa?. All patients were analyzed for tumour response, progression free survival as well as for toxicity. X2 test, Kaplan Meiers curves and Log rank test were used for statistical analysis. Results. Although the recorded response rates were a bit lower than in previously published trials, they were not significantly different p=0.485. No statistically significant difference was recorded in either progression free survival or overall survival. The chemotherapeutical Cisplatin/Etoposide protocol proved to be more toxic both in hematologic (3% vs. 10%) and total toxicities (p=0.047). Conclusion. Our study proved both protocols to have equivalent efficacy. However, the Cisplatin, Vinorelbine protocol could be recommended because of its less expressed toxic effects.

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EGFR Exon 18 Mutations in Advanced Non-Small Cell Lung Cancer: A Real-World Study on Diverse Treatment Patterns and Clinical Outcomes

Frontiers in Oncology ◽

10.3389/fonc.2021.713483 ◽

2021 ◽

Vol 11 ◽

Author(s):

Haiyan Xu ◽

Guangjian Yang ◽

Weihua Li ◽

Junling Li ◽

Xuezhi Hao ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Clinical Outcomes ◽

Cell Lung Cancer ◽

Kinase Inhibitor ◽

Progression Free Survival ◽

Small Cell ◽

Small Cell Lung ◽

Effective Treatment Option ◽

Significant Difference

BackgroundApproximately 3–5% of patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) harbor exon 18 mutations. The appropriate treatment for such patients has not been clarified. The aim of this study was to investigate the response of patients with NSCLC harboring EGFR exon 18 mutations to different therapeutic options.MethodsBetween May 2014 and September 2020, the clinical outcomes of 82 patients harboring EGFR exon 18 mutations who received first-generation (1G) EGFR-tyrosine kinase inhibitor (TKI), second-generation (2G) EGFR-TKI afatinib, chemotherapy, and 1G TKI in combination with chemotherapy as the initial therapy were retrospectively analyzed.ResultsA total of 82 NSCLC patients harboring EGFR 18 mutations with whose treatment and survival outcomes were available were analyzed. The median age was 59 years, and 47 (57.3%) were female. The most common kind of EGFR exon 18 mutation was G719X (75.6%), followed by E709X (15.9%), E709_T710delinsD (3.6%), and other subtypes (4.9%). There was a significant difference in median progression-free survival (mPFS) by therapeutic strategy (P = 0.017). The mPFS of 1G TKI, 2G TKI afatinib, chemotherapy, and 1G TKI in combination with chemotherapy were 7.7 (95% CI, 4.2–11.2), 11.3 (95% CI, 5.6–17.0), 5.0 (95% CI, 2.3–17.7), and 11.1 (95% CI, 5.9–16.4) months, respectively. No significant difference in PFS was observed between afatinib and 1G TKI in combination with chemotherapy (P = 0.709).ConclusionsLike afatinib, 1G TKI in combination with chemotherapy might be an effective treatment option for patients harboring EGFR exon 18 mutations.

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P84.20 VATS Right Upper Lobectomy for Advanced Non-Small Cell Lung Cancer After ALK-Tyrosine Kinase Inhibitor Administration.

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2021.01.1219 ◽

2021 ◽

Vol 16 (3) ◽

pp. S666-S667

Author(s):

K. Yamamoto ◽

M. Kuwahara ◽

S. Yamamoto

Keyword(s):

Lung Cancer ◽

Tyrosine Kinase ◽

Small Cell Lung Cancer ◽

Tyrosine Kinase Inhibitor ◽

Cell Lung Cancer ◽

Kinase Inhibitor ◽

Small Cell ◽

Small Cell Lung

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Digital Pathology and PD-L1 Testing in Non Small Cell Lung Cancer: A Workshop Record

Cancers ◽

10.3390/cancers12071800 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1800 ◽

Cited By ~ 2

Author(s):

Fabio Pagni ◽

Umberto Malapelle ◽

Claudio Doglioni ◽

Gabriella Fontanini ◽

Filippo Fraggetta ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Gold Standard ◽

Digital Pathology ◽

Small Cell ◽

Small Cell Lung ◽

Significant Difference ◽

Standard Quality ◽

A Minor

A meeting among expert pathologists was held in 2019 in Rome to verify the results of the previous harmonization efforts on the PD-L1 immunohistochemical testing by scoring a representative series of non-small cell lung cancer (NSCLC) digital slides. The current paper shows the results of this digital experimental meeting and the expertise achieved by the community of Italian pathologists. PD-L1 protein expression was determined using tumor proportion score (TPS), i.e., the percentage of viable tumor cells showing partial or complete membrane staining at any intensity. The gold standard was defined as the final PD-L1 score formulated by a panel of seven lung committed pathologists. PD-L1 status was clustered in three categories, namely negative (TPS < 1), low (TPS 1–49%), and high (TPS ≥ 50%). In 23 cases (71.9%) PD-L1 staining was performed using the companion diagnostic 22C3 pharmDx kit on Dako Autostainer, while in nine (28.1%) cases it was performed using the SP263 Ventana kit on BenchMark platform. A complete PD-L1 scoring agreement between the panel of experts and the participants was reached in 57.1% of cases, whereas a minor disagreement in 16.1% of cases was recorded. Italian pathologists performed best in strong positive cases (i.e., tumor proportion score TPS > 50%), whereas only 10.8% of disagreement with the gold standard was observed, and 55.6% regarded a single challenging case. The worst performance was achieved in the negative cases, with 32.0% disagreement. A significant difference resulted from the analysis of the data separated by the different clones used: 22.3% and 38.1% disagreement (p = 0.01) was found in the group of cases analyzed by 22C3 and SP263 antibody clones, respectively. In conclusion, this workshop record proposed the application of a digital pathology platform to share controversial cases in educational meetings as an alternative possibility for improving the interpretation and reporting of specific histological tools. Due to the crucial role of PD-L1 TPS for the selection of patients for immunotherapy, the identification of unconventional approaches as virtual slides to focus experiences and give more detailed practical verifications of the standard quality reached may be a considerable option.

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A phase II trial of the Src-kinase inhibitor saracatinib after four cycles of chemotherapy for patients with extensive stage small cell lung cancer: NCCTG trial N-0621

Lung Cancer ◽

10.1016/j.lungcan.2014.03.004 ◽

2014 ◽

Vol 85 (2) ◽

pp. 245-250 ◽

Cited By ~ 26

Author(s):

Julian R. Molina ◽

Nathan R. Foster ◽

Thanyanan Reungwetwattana ◽

Garth D. Nelson ◽

Andrew V. Grainger ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Phase Ii ◽

Cell Lung Cancer ◽

Kinase Inhibitor ◽

Phase Ii Trial ◽

Src Kinase ◽

Small Cell ◽

Small Cell Lung ◽

Extensive Stage

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Transient asymptomatic pulmonary opacities and interstitial lung disease in EGFR-mutated non-small cell lung cancer treated with osimertinib

Tumori Journal ◽

10.1177/03008916211047888 ◽

2021 ◽

pp. 030089162110478

Author(s):

Gianluca Taronna ◽

Alessandro Leonetti ◽

Filippo Gustavo Dall’Olio ◽

Alessandro Rizzo ◽

Claudia Parisi ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Clinical Outcomes ◽

Cell Lung Cancer ◽

Small Cell ◽

Clinical Variable ◽

Small Cell Lung ◽

Significant Difference ◽

Egfr Mutated

Introduction: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved as first-line therapy for advanced EGFR-mutated non-small cell lung cancer (NSCLC). Some osimertinib-related interstitial lung diseases (ILDs) were shown to be transient, called transient asymptomatic pulmonary opacities (TAPO)—clinically benign pulmonary opacities that resolve despite continued osimertinib treatment—and are not associated with the clinical manifestations of typical TKI-associated ILDs. Methods: In this multicentric study, we retrospectively analyzed 92 patients with EGFR-mutated NSCLC treated with osimertinib. Computed tomography (CT) examinations were reviewed by two radiologists and TAPO were classified according to radiologic pattern. We also analyzed associations between TAPO and patients’ clinical variables and compared clinical outcomes (time to treatment failure and overall survival) for TAPO-positive and TAPO-negative groups. Results: TAPO were found in 18/92 patients (19.6%), with a median follow-up of 114 weeks. Median onset time was 16 weeks (range 6–80) and median duration time 14 weeks (range 8–37). The most common radiologic pattern was focal ground-glass opacity (54.5%). We did not find any individual clinical variable significantly associated with the onset of TAPO or significant difference in clinical outcomes between TAPO-positive and TAPO-negative groups. Conclusions: TAPO are benign pulmonary findings observed in patients treated with osimertinib. TAPO variability in terms of CT features can hinder the differential diagnosis with either osimertinib-related mild ILD or tumor progression. However, because TAPO are asymptomatic, it could be reasonable to continue therapy and verify the resolution of the CT findings at follow-up in selected cases.

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Adjuvant gefitinib versus cisplatin/vinorelbine in Japanese patients with completely resected, EGFR-mutated, stage II-III non-small cell lung cancer (IMPACT, WJOG6410L): A randomized phase 3 trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.8501 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 8501-8501

Author(s):

Hirohito Tada ◽

Tetsuya Mitsudomi ◽

Takeharu Yamanaka ◽

Kenji Sugio ◽

Masahiro Tsuboi ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Egfr Mutation ◽

Disease Free Survival ◽

Small Cell ◽

Stage Ii ◽

Small Cell Lung ◽

Significant Difference ◽

Egfr Mutated

8501 Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor is a standard of care for EGFR mutation-positive, untreated metastatic non-small cell lung cancer (NSCLC). However, the efficacy and safety of adjuvant gefitinib for patients with completely resected lung cancer harboring EGFR mutation over cisplatin-based adjuvant chemotherapy were not known in 2011 when this study was initiated. Methods: From September 2011 to December 2015, we randomly assigned 234 patients with completely resected, EGFR mutation-positive (exon 19 deletion or L858R), stage II–III NSCLC to receive either gefitinib (250 mg, once daily) for 24 months or cisplatin (80 mg/m2 on day 1) plus vinorelbine (25 mg/m2 on days 1 and 8) (cis/vin) every 3 weeks for four cycles. The primary endpoint was disease-free survival (DFS) according to a central review in the intent-to-treat (ITT) population. Results: Two patients in the gefitinib arm withdrew consent and were excluded from the ITT population. No treatment-related deaths were seen in the gefitinib arm, but three treatment-related deaths were reported in the cis/vin arm. Median duration of follow-up was 71 months. Median DFS was numerically longer in the gefitinib arm (36 months) than in the cis/vin arm (25.2 months). However, Kaplan-Meier curves began to overlap around 5 years after surgery, and no significant difference in DFS was seen, with a hazard ratio (HR) of 0.92 (95% confidence interval (CI), 0.67–1.28; P = 0.63). Overall survival was also not significantly different (median not reached in either arm). Five-year survival rates for gefitinib and cis/vin arms were 78.0% and 74.6%, respectively, with an HR for death of 1.03; 95%CI, 0.65–1.65; P = 0.89. Exploratory subset analysis revealed that patients ³70 years old in the gefitinib arm (n = 19/27 with G to cis/vin) survived longer than those in the cis/vin arm (HR 0.31; 95%CI, 0.10–0.98; P = 0.046). Conclusions: Adjuvant gefitinib appeared to prevent early relapse, but did not significantly prolong DFS or OS in patients with completely resected stage II–III, EGFR-mutated NSCLC. The apparent non-inferiority of DFS/OS may justify the use of adjuvant gefitinib in selected subset of patients, especially those deemed unsuitable for cis/vin adjuvant therapy. Clinical trial information: UMIN000006252.

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