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

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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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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Clinical outcomes of various resistance mechanisms of osimertinib in Chinese advanced non-small cell lung cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e20530 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e20530-e20530

Author(s):

Puyuan Xing ◽

Li Junling ◽

Xuezhi Hao ◽

Yuxin Mu ◽

Shouzheng Wang ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Clinical Outcomes ◽

Cell Lung Cancer ◽

Progression Free Survival ◽

Resistance Mechanisms ◽

Small Cell ◽

Egfr Mutations ◽

Small Cell Lung ◽

Kras Mutations

e20530 Background: Increasing efforts have been invested in elucidating the resistance mechanisms to osimertinib. Major resistance mechanisms include but not limited to acquired EGFR mutations, predominantly C797, mutations in bypass pathways and small cell lung cancer (SCLC) transformation. However, no study has comprehensively investigated clinical outcomes of various mechanisms of resistance. Methods: 103 T790M positive advanced Chinese non-small cell lung cancer (NSCLC) patients who progressed on 1st generation EGFR-TKI were enrolled. Targeted sequencing, using a panel consisting of 168 lung cancer related genes, was performed on paired plasma samples collected prior to osimertinib and after the development of disease progression (PD) to profile mutation spectrum. 7 patients with no mutation detected at PD were excluded from analyses. Results: Major acquired mutations included 25% EGFR mutations, predominantly C797 and L792, 16% MET amplification, 8% TP53 mutations, 4% KRAS mutations, 4% RET fusions, 4% ERBB2 amplification and 6.25% RB1 mutations. Acquired RB1 mutation may indicate the possibility of SCLC transformation. Approximately, 30% of patients with no known resistance mechanisms at PD. In this cohort, we had 61 patients with 19 deletion and 35 patients with EGFR L858R prior to the initiation of osimertinib. We revealed patients with 19del acquired more mutations ( p= 0.014) and were more likely to acquire mutations in MAP/PI3Kpathway ( p= 0.04) and TP53 at PD ( p= 0.021). On the other hand, acquired ERBB2 amplifications were only detected in L858R-mutant patients ( p= 0.047). Furthermore, 36 patients preserved T790M and 60 patients lost T790M at PD. Our data revealed patients retaining T790M, often associated with activation of bypass signaling pathways or continued EGFR activation through tertiary mutations, had a longer progression-free survival (PFS) ( p= 0.047) and overall survival (OS) ( p= 0.04) comparing to patients with T790M loss, often with diverse and EGFR-independent mechanisms. We also show that patients with acquired C797S had significantly longer PFS ( p= 0.031), while patients with acquired MET amplifications had significantly shorter PFS ( p= 0.033). Conclusions: Collectively, we revealed differential clinical outcomes associated with various resistance mechanisms, representing an important step in advancing the understanding of resistance mechanisms of osimertinib.

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Treatment outcome and safety of anti-PD-1 antibody against elderly non-small cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14249 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14249-e14249

Author(s):

Toshio Sakatani ◽

Aya Saihara ◽

Hiroaki Ikushima ◽

Hideyuki Takeshima ◽

Yuri Taniguchi ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Elderly People ◽

Cell Lung Cancer ◽

Antibody Therapy ◽

Progression Free Survival ◽

The Elderly ◽

Small Cell ◽

Small Cell Lung ◽

Significant Difference

e14249 Background: The anti-PD-1 antibodies, Pembrolizumab (Pem) and Nivolumab (Nivo), have become available for practical clinical use in Japan, and many patients are benefiting from them. Lung cancer is predominantly a disease of the elderly people. However, the validity and safety of anti-PD-1 antibodies against the elderly are insufficient. Methods: From February 2016 to November 2018, 66 patients with non-small cell lung cancer who received anti-PD-1 antibody therapy (23 Pem and 43 Nivo) were evaluated for progression-free survival (PFS), overall survival (OS), and safety were compared between groups between the aged ≥75 years (≥75 yrs) and < 75 years ( < 75 yrs). Results: The median age (width) was 67 years (46-87 years). 46 patients were < 75 yrs and 20 patients were ≥75 yrs. PFS was 3.3 months (m) vs. 4.4 m ( < 75 yrs vs. ≥75 yrs)(p = 0.214). OS was 11.7 m vs. 16.7 m ( < 75 yrs vs. ≥75 yrs)(p = 0.212). Similar analysis was carried out for each anti-PD-1 antibody. In Pem, 15 patients were < 75 yrs and 8 patients were ≥75 yrs, and there was no significant difference between PFS and OS (p = 0.46, p = 0.17, respectively). In Nivo, 31 patients < 75 yrs, 12 patietns > 75 yrs, and there was no significant difference in PFS and OS (p = 0.49, p = 0.44, respectively). Immunity-related adverse events (irAE) was expressed in 25 patients (37.9%). Among 66 patients, 19 in 46 (41%) were < 75 yrs, 6 in 20 (30%) were ≥75yrs. There were not many irAEs even in the elderly people (χ2= 0.757, p = 0.384). Conclusions: Pem and Nivo proved to be effective and safe for the elderly patients even in the clinical setting.

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Impact of SWI/SNF complex mutations in patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors: Immuno-oncology biomarker study in LC-SCRUM-Japan (LC-SCRUM-IBIS).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.9530 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 9530-9530

Author(s):

Kiyotaka Yoh ◽

Shingo Matsumoto ◽

Naoki Furuya ◽

Kazumi Nishino ◽

Shingo Miyamoto ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Clinical Outcomes ◽

Cell Lung Cancer ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Progression Free Survival ◽

Small Cell ◽

Small Cell Lung ◽

Nsclc Patients

9530 Background: The SWI/SNF chromatin remodeling complex is reported to be involved in sensitivity and resistance to immune checkpoint inhibitor (ICI). However, their role in non-small cell lung cancer (NSCLC) remains unclear. We examined the relationship between SWI/SNF complex mutations and clinical outcomes of ICI in patients with NSCLC. Methods: Of 1017 lung cancer patients enrolled in LC-SCRUM-IBIS, 350 patients were analyzable for whole-exome sequencing (WES). WES data were used to analyze the presence of mutations in 29 major subunits of the SWI/SNF complexes. ARID1A and SMARCA4 mutations were also evaluated in a targeted NGS panel (Oncomine comprehensive assay, OCA). PD-L1 expression by 22C3, tissue tumor mutational burden (tTMB) by WES, STK11 and KEAP1 mutations by WES or OCA were also assessed. Durable clinical benefit (DCB) including CR, PR and SD > 6 mos to ICI, progression-free survival (PFS) and overall survival (OS) were compared in status of each of SWI/SNF complex mutations and other factors. Results: At least one mutation in any subunits of the SWI/SNF complex was present in 28% of NSCLC patients. The most common mutated subcomplexes were SMARCA4 (12%), BAF (7%: ARID1A, 4%), non-canonical BAF (3%), PBAF (3%), and SMARCA2 (2%). Of 101 NSCLC patients treated with PD-1/PD-L1 inhibitors, SMARCA4 mutations tended to be associated with lower DCB (16 vs 31%) and shorter median PFS (1.9 vs 3.6 m) and OS (7.4 vs 18.1m). Patients with ARID1A mutations tended to have better clinical outcomes (DCB, 40 vs 28%) compared to those without mutations. No significant associations were found between PD-L1 expression and SMARCA4 or ARID1A mutations. Patients with STK11/KEAP1 mutations had lower rate of PD-L1 expression (TPS > 50%) (18% vs 48%, P = 0.03) and worse clinical outcomes (DCB, 6 vs 33%) compared to those without mutations. There was no significant association between a tTMB status and clinical outcome. Conclusions: SMARCA4 and ARID1A mutations appear to affect clinical outcomes of ICI in NSCLC patients. These findings indicate that SWI/SNF complex mutations may serve as a predictive biomarker for ICI in NSCLC patients.

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Immune Checkpoint Inhibitor Outcomes for Patients With Non–Small-Cell Lung Cancer Receiving Baseline Corticosteroids for Palliative Versus Nonpalliative Indications

Journal of Clinical Oncology ◽

10.1200/jco.19.00189 ◽

2019 ◽

Vol 37 (22) ◽

pp. 1927-1934 ◽

Cited By ~ 58

Author(s):

Biagio Ricciuti ◽

Suzanne E. Dahlberg ◽

Anika Adeni ◽

Lynette M. Sholl ◽

Mizuki Nishino ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Progression Free Survival ◽

Small Cell ◽

Small Cell Lung ◽

Corticosteroid Administration ◽

Programmed Cell Death 1 ◽

Significant Difference ◽

Poor Outcomes

PURPOSE Baseline use of corticosteroids is associated with poor outcomes in patients with non–small-cell lung cancer (NSCLC) treated with programmed cell death-1 axis inhibition. To approach the question of causation versus correlation for this association, we examined outcomes in patients treated with immunotherapy depending on whether corticosteroids were administered for cancer-related palliative reasons or cancer-unrelated indications. PATIENTS AND METHODS Clinical outcomes in patients with NSCLC treated with immunotherapy who received ≥ 10 mg prednisone were compared with outcomes in patients who received 0 to < 10 mg of prednisone. RESULTS Of 650 patients, the 93 patients (14.3%) who received ≥ 10 mg of prednisone at the time of immunotherapy initiation had shorter median progression-free survival (mPFS) and median overall survival (mOS) times than patients who received 0 to < 10 mg of prednisone (mPFS, 2.0 v 3.4 months, respectively; P = .01; mOS, 4.9 v 11.2 months, respectively; P < .001). When analyzed by reason for corticosteroid administration, mPFS and mOS were significantly shorter only among patients who received ≥ 10 mg prednisone for palliative indications compared with patients who received ≥ 10 mg prednisone for cancer-unrelated reasons and with patients receiving 0 to < 10 mg of prednisone (mPFS, 1.4 v 4.6 v 3.4 months, respectively; log-rank P < .001 across the three groups; mOS, 2.2 v 10.7 v 11.2 months, respectively; log-rank P < .001 across the three groups). There was no significant difference in mPFS or mOS in patients receiving ≥ 10 mg of prednisone for cancer-unrelated indications compared with patients receiving 0 to < 10 mg of prednisone. CONCLUSION Although patients with NSCLC treated with ≥ 10 mg of prednisone at the time of immunotherapy initiation have worse outcomes than patients who received 0 to < 10 mg of prednisone, this difference seems to be driven by a poor-prognosis subgroup of patients who receive corticosteroids for palliative indications.

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Randomized Trial of Afatinib Plus Cetuximab Versus Afatinib Alone for First-Line Treatment of EGFR-Mutant Non–Small-Cell Lung Cancer: Final Results From SWOG S1403

Journal of Clinical Oncology ◽

10.1200/jco.20.01149 ◽

2020 ◽

Vol 38 (34) ◽

pp. 4076-4085

Author(s):

Sarah B. Goldberg ◽

Mary W. Redman ◽

Rogerio Lilenbaum ◽

Katerina Politi ◽

Thomas E. Stinchcombe ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Kinase Inhibitor ◽

Acquired Resistance ◽

Progression Free Survival ◽

Multicenter Trial ◽

Small Cell ◽

Small Cell Lung ◽

Egfr Mutant

PURPOSE The irreversible ErbB family tyrosine kinase inhibitor (TKI) afatinib plus the EGFR monoclonal antibody cetuximab was previously shown to overcome resistance to EGFR TKIs. We studied whether the combination of afatinib plus cetuximab compared with afatinib alone would improve progression-free survival (PFS) in patients with treatment-naive EGFR-mutant non–small-cell lung cancer (NSCLC) by preventing or delaying resistance. METHODS Patients with EGFR-mutant NSCLC without prior treatment of advanced disease were enrolled in this phase II, multicenter trial and randomly assigned to receive afatinib 40 mg orally daily plus cetuximab 500 mg/m2 intravenously every 2 weeks or afatinib alone. The primary end point was PFS. RESULTS Between March 25, 2015 and April 23, 2018, 174 patients were randomly assigned, and 168 (83 on afatinib + cetuximab and 85 on afatinib) were eligible. There was no improvement in PFS in patients receiving afatinib plus cetuximab compared with afatinib alone (hazard ratio [HR], 1.01; 95% CI, 0.72 to 1.43; P = .94; median, 11.9 months v 13.4 months). Similarly, there was no difference in response rate (67% v 74%; P = .38) or overall survival (HR, 0.82; 95% CI, 0.50 to 1.36; P = .44). Toxicity was greater with the combination: grade ≥ 3 adverse events related to treatment occurred in 72% of patients receiving afatinib plus cetuximab compared with 40% of those receiving afatinib alone, most commonly rash and diarrhea. Dose reductions were more common in patients receiving the combination, and 30% of patients in this arm discontinued cetuximab due to toxicity. At interim analysis, there was insufficient evidence to support continued accrual, and the trial was closed. CONCLUSIONS The addition of cetuximab to afatinib did not improve outcomes in previously untreated EGFR-mutant NSCLC, despite recognized activity in the acquired resistance setting.

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Real-world characteristics and outcomes of advanced non-small-cell lung cancer patients with EGFR exon 19 deletions or exon 21 mutations

Future Oncology ◽

10.2217/fon-2021-0218 ◽

2021 ◽

Author(s):

Katherine B Winfree ◽

Cliff Molife ◽

Patrick M Peterson ◽

Yongmei Chen ◽

Carla M Visseren-Grul ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Real World ◽

Egf Receptor ◽

Kinase Inhibitor ◽

Progression Free Survival ◽

Small Cell ◽

Small Cell Lung ◽

First Line Therapy

Aim: To estimate real-world (rw) outcomes for first-line therapy in patients with advanced EGF receptor ( EGFR)-mutated non-small-cell lung cancer (NSCLC), focusing on specific mutation types. Patients & methods: Retrospective observational study (n = 244 patients). Results: Univariate/multivariate analyses showed longer rw progression-free survival (rwPFS) and rwPFS2 in patients with ex19del versus Leu858Arg mutations. Median overall survival was 12.3 months longer with ex19del versus Leu858Arg mutations (HR: 1.47 [95% CI: 0.96–2.25]; p = 0.074). With EGFR-tyrosine kinase inhibitor monotherapy, unadjusted rwPFS for ex19del mutations was longer than for Leu858Arg mutations (HR: 1.62 [95% CI: 1.03–2.56]; p = 0.036). Conclusion: In this rw cohort of patients with advanced EGFR+ NSCLC, ex19del mutations conferred a prognostic advantage over Leu858Arg mutations, with significantly better rwPFS and rwPFS2.

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Clinical Outcomes in Non–Small-Cell Lung Cancer Patients Treated With EGFR-Tyrosine Kinase Inhibitors and Other Targeted Therapies Based on Tumor Versus Plasma Genomic Profiling

JCO Precision Oncology ◽

10.1200/po.20.00532 ◽

2021 ◽

pp. 1241-1249

Author(s):

Hai T. Tran ◽

Vincent K. Lam ◽

Yasir Y. Elamin ◽

Lingzhi Hong ◽

Rivka Colen ◽

...

Keyword(s):

Lung Cancer ◽

Tyrosine Kinase ◽

Small Cell Lung Cancer ◽

Clinical Outcomes ◽

Cell Lung Cancer ◽

Progression Free Survival ◽

Small Cell ◽

Small Cell Lung ◽

Free Survival ◽

Egfr Tyrosine Kinase

PURPOSE To compare clinical outcomes in a cohort of patients with advanced non–small-cell lung cancer (NSCLC) with targetable genomic alterations detected using plasma-based circulating tumor DNA (ctDNA) or tumor-based next-generation sequencing (NGS) assays treated with US Food and Drug Administration–approved therapies at a large academic research cancer center. METHODS A retrospective review from our MD Anderson GEMINI database identified 2,224 blood samples sent for ctDNA NGS testing from 1971 consecutive patients with a diagnosis of advanced NSCLC. Clinical, treatment, and outcome information were collected, reviewed, and analyzed. RESULTS Overall, 27% of the ctDNA tests identified at least one targetable mutation and 73% of targetable mutations were EGFR-sensitizing mutations. Among patients treated with first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapies, there were no significant differences in progression-free survival of 379 days and 352 days ( P value = .41) with treatment based on tissue (n = 40) or ctDNA (n = 40), respectively. Additionally, there were no differences in progression-free survival or objective response rate among those with low (n = 8, 0.01%-0.99%) versus high (n = 16, ≥ 1%) levels of ctDNA of the targetable mutation as measured by variant allele frequency (VAF). Overall, there was excellent testing concordance (n = 217 tests) of > 97%, sensitivity of 91.7%, and specificity of 99.7% between blood-based ctDNA NGS and tissue-based NGS assays. CONCLUSION There were no significant differences in clinical outcomes among patients treated with approved EGFR-TKIs whose mutations were identified using either tumor- or plasma-based comprehensive profiling and those with very low VAF as compared with high VAF, supporting the use of plasma-based profiling to guide initial TKI use in patients with metastatic EGFR-mutant NSCLC.

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

Cancers ◽

10.3390/cancers11101431 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1431 ◽

Cited By ~ 3

Author(s):

Abate ◽

Pasquale ◽

Sacco ◽

Piccirillo ◽

Morabito ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

First Generation ◽

Kinase Inhibitor ◽

Small Cell ◽

Rank Test ◽

Small Cell Lung ◽

Single Nucleotide Variants ◽

Significant Difference

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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A pilot study of nintedanib in molecularly selected patients with advanced non-small cell lung cancer (NSCLC) (NCT02299141).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e21694 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e21694-e21694

Author(s):

Saiama Naheed Waqar ◽

Usha Rawat ◽

Daniel Morgensztern ◽

Sanjana Shah ◽

Jeffrey P. Ward ◽

...

Keyword(s):

Lung Cancer ◽

Pilot Study ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Kinase Inhibitor ◽

Progression Free Survival ◽

Small Cell ◽

Small Cell Lung ◽

Open Label ◽

Free Survival

e21694 Background: Nintedanib is a small molecule tyrosine kinase inhibitor targeting VEGFR1-3, PDGFR and FGFR. The purpose of the study was to evaluate the response rate for patients with advanced non-small cell lung cancer (NSCLC) with mutations in TP53, VEGFR1-3, PDGFR-A, PDGFR-B, and FGFR1-3 treated with nintedanib as part of an open label, single arm pilot study. Methods: Patients with advanced NSCLC previously treated with platinum-doublet chemotherapy with ECOG PS≤1 and adequate organ function were enrolled. Exclusion criteria included cavitary or necrotic tumors with invasion of major blood vessels, history of recent thromboembolic events, predisposition to bleeding or thrombosis, myocardial infarction and weight loss > 10% within past 6 months. Nintedanib was administered at a dose of 200 mg orally twice daily during each 28-day cycle until disease progression or unacceptable toxicity. Response assessments were performed every 8 weeks. The primary endpoint was overall response (ORR) by RECIST 1.1. Secondary endpoints included progression-free survival (PFS) and correlating outcomes with specific mutations. Results: Between 5/7/2015 and 11/15/2019, 20 patients were enrolled to study. The median age was 66 years, 15/20 (75% were females), 17/20 (85%) had received prior immunotherapy and 11/20 (55%) had received at least three prior lines of systemic therapy. The ORR was 15% with 3/20 partial responses (PR), while 12 patients had stable disease (SD), with disease control (PR+SD≥16 weeks) rate of 60% (12/20). The median progression-free survival and median overall survival were 18 weeks (95% CI: 8-31) and 48 weeks (95% CI:15-56) respectively. All three responders had a TP53 mutation and had received prior immunotherapy. There were nine grade 3 events including transaminitis in 20%, while one patient each (5%) experienced hyperbilirubinemia, anorexia, fatigue, hypertension, and nausea. Grade 4 events included transaminitis (10%) and cerebral edema (5%). There was one grade 5 cardiac event, which was unrelated to nintedanib. Conclusions: In this pilot study in heavily pretreated and molecularly selected patients with metastatic NSCLC, nintedanib showed modest activity. Clinical trial information: NCT02299141.

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