RET rearrangements detected by FISH in “pan-negative” lung adenocarcinoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8024-8024 ◽  
Author(s):  
Marileila Varella-Garcia ◽  
Liang Guo Xu ◽  
Sakshi Mahale ◽  
Eamon M Berge ◽  
Chiara Bennati ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Inhibitors ◽  
Molecular Subtype ◽  
Stage Iv ◽  
Stage Iv Disease ◽  
Heavily Pretreated ◽  
Target Fish ◽  
Never Smokers ◽  
Practice Methods ◽  
Lung Adenocarcinomas

8024 Background: RET rearrangements have recently been reported in NSCLC and there is pre-clinical evidence that RET tyrosine kinase inhibitors (TKIs) block activated RET kinase. Efficient and accurate detection of RET rearrangements are crucial for the success of RET TKIs in clinical trials. RET rearrangements have been detected by specialized sequencing techniques with limited applicability to clinical practice. Methods: A 3-target FISH probe set was developed to detect KIF5B-RET fusions and identify patterns suggestive of RET rearrangements with non-KIF5B partners. 51 lung adenocarcinomas negative for EGFR, KRAS, ALK and ROS1 (36 were also negative for 7 other molecular markers) were investigated. Clinical and demographic characteristics were collected. Results: Eight patients (15%) had rearrangements in the RET gene: 5 with KIF5B-RET fusions, 2 with patterns consistent with the CCDC6-RET fusion, and 1 with extra copies of single 3’RET (loss of 5’RET). Atypical FISH patterns were detected both in RET + and negative specimens suggesting high genomic instability in the KIF5B – RET region. RT-PCR assay determined the exon/fusion variant in 4 cases including 2 patients with K15:R12, 1 with K16:R12 and 1 with C1:R12. Median age at diagnosis was 58.5 in the mutation negative and 63 in the RET+ patients. Both cohorts were predominantly male (66% and 56%, respectively), with a majority of never smokers (59 and 89%, respectively), and stage IV disease at diagnosis (72 and 89%, respectively). Two heavily pretreated RET+ patients had stable disease at their initial restaging scans following treatment with the RET inhibitor vandetanib (radiographic assessment per RECIST 1.1); two others had early radiographic progression with sunitinib. Conclusions: The FISH probe proved efficient to detect RET rearrangements in lung adenocarcinomas, involving KIF5B and non-KIF5B partners. Frequency of RET rearrangements in this enriched lung adenocarcinoma cohort was considerably higher than reported in unselected cohorts. Further molecular analyses are being performed to increase understanding of the natural history of this new molecular subtype of NSCLC. Support: B J Addario Foundation, NCI P50CA058187, NCI CCSG P30CA046934.

scholarly journals Complete Response to Afatinib of an EGFR Exon 18 delE709_T710insD-Mutated Stage IV Lung Adenocarcinoma

2021 ◽  
Author(s):  
Blandine Jelli ◽  
Olivier Taton ◽  
Nicky D'Haene ◽  
Myriam Remmelink ◽  
Zita Mekinda
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Stage Iv ◽  
Complete Response ◽  
Egfr Mutations ◽  
First Case ◽  
Treatment Interruptions ◽  
Patient Prognosis ◽  
Lung Adenocarcinomas

Introduction: Epidermal growth factor receptor (EGFR) mutations are frequently found in patients with lung adenocarcinomas, 90% being deletions in exon 19 or point mutation in exon 21. Three generations of tyrosine kinase inhibitors (TKIs) targeting EGFR mutations are available and have changed patient prognosis but less data is available on exon 18 mutations and their sensitivity to TKI therapy. Exon 18 delE709_T710insD accounts for 0.06% (16/27,294) of all EGFR mutations and is an oncogenic driver. Several partial responses to afatinib have been described. Case description: We report the first case, to the best of our knowledge, of the complete response to afatinib of a 57-year-old patient with stage IV lung adenocarcinoma with a delE709_T710insD mutation in the EGFR gene detected by next-generation sequencing. Oral afatinib was prescribed and despite treatment interruptions and dosage tapering due to cutaneous adverse events, a complete response was achieved 12 months after treatment initiation and is currently maintained at 17 months. Conclusion: When EGFR mutation is suspected, complete DNA sequencing of exons 18 to 21 should be carried out and we suggest that afatinib should be the first-line treatment for exon 18 delE709_T710insD-mutated advanced lung adenocarcinomas.

Crizotinib Therapy for Advanced Lung Adenocarcinoma and a ROS1 Rearrangement: Results From the EUROS1 Cohort

2015 ◽  
Vol 33 (9) ◽  
pp. 992-999 ◽  
Author(s):  
Julien Mazières ◽  
Gérard Zalcman ◽  
Lucio Crinò ◽  
Pamela Biondani ◽  
Fabrice Barlesi ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Response Rate ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Highly Active ◽  
Best Response ◽  
Ros1 Rearrangement ◽  
Never Smokers ◽  
Lung Adenocarcinomas

Purpose Approximately 1% of lung adenocarcinomas are driven by oncogenic ROS1 rearrangement. Crizotinib is a potent inhibitor of both ROS1 and ALK kinase domains. Patients and Methods In the absence of a prospective clinical trial in Europe, we conducted a retrospective study in centers that tested for ROS1 rearrangement. Eligible patients had stage IV lung adenocarcinoma, had ROS1 rearrangement according to fluorescent in situ hybridization, and had received crizotinib therapy through an individual off-label use. Best response was assessed locally using RECIST (version 1.1). All other data were analyzed centrally. Results We identified 32 eligible patients. One patient was excluded because next-generation sequencing was negative for ROS1 fusion. Median age was 50.5 years, 64.5% of patients were women, and 67.7% were never-smokers. Thirty patients were evaluable for progression-free survival (PFS), and 29 patients were evaluable for best response. We observed four patients with disease progression, two patients with stable disease, and objective response in 24 patients, including five complete responses (overall response rate, 80%; disease control rate, 86.7%). Median PFS was 9.1 months, and the PFS rate at 12 months was 44%. No unexpected adverse effects were observed. Twenty-six patients received pemetrexed (either alone or in combination with platinum and either before or after crizotinib) and had a response rate of 57.7% and a median PFS of 7.2 months. Conclusion Crizotinib was highly active at treating lung cancer in patients with a ROS1 rearrangement, suggesting that patients with lung adenocarcinomas should be tested for ROS1. Prospective clinical trials with crizotinib and other ROS1 inhibitors are ongoing or planned.

scholarly journals Better Progression-Free Survival in Elderly Patients with Stage IV Lung Adenocarcinoma Harboring Uncommon Epidermal Growth Factor Receptor Mutations Treated with the First-line Tyrosine Kinase Inhibitors

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 434 ◽  
Author(s):  
Ming-Ju Tsai ◽  
Jen-Yu Hung ◽  
Mei-Hsuan Lee ◽  
Chia-Yu Kuo ◽  
Yu-Chen Tsai ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
First Line ◽  
Free Survival ◽  
Younger Patients ◽  
Epidermal Growth

Patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutations usually have a good response rate (RR) and longer progression-free survival (PFS) to EGFR tyrosine kinase inhibitors (TKIs). However, the treatment efficacy to uncommon EGFR mutations remains controversial. We, therefore, performed a retrospective study, screening 2958 patients. A total of 67 patients with lung adenocarcinoma harboring uncommon EGFR mutations were enrolled and 57 patients with stage IV diseases receiving a first-line EGFR TKI were included for further analyses. The patients were classified into 27 (47%) “a single sensitizing uncommon mutation”, 7 (12%) “multiple sensitizing mutations”, 5 (9%) “a sensitizing mutation and a resistant uncommon mutation”, and 18 (32%) “other resistant uncommon mutations”. No significant difference was noted in PFS or overall survival (OS) between groups. Patients receiving different first-line EGFR TKIs had similar PFS and OS. The elder patients had a significantly poorer performance status than the younger patients but a significantly longer PFS than the younger patients (median PFS: 10.5 vs. 5.5 months, p = 0.0320). In conclusion, this is the first study to identify that elderly patients with stage IV lung adenocarcinoma harboring uncommon EGFR mutation might have a longer PFS. Large-scale prospective studies are mandatory to prove our findings.

Geriatric assessment of older adults with cancer: Baseline data from a 500 patient multicenter study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9546-9546 ◽  
Author(s):  
A. Hurria ◽  
S. Mohile ◽  
S. Lichtman ◽  
C. Owusu ◽  
H. Klepin ◽  
...  
Keyword(s):  
Older Adults ◽  
Geriatric Assessment ◽  
Stage Iv ◽  
Morbidity And Mortality ◽  
Psychological Status ◽  
The Past ◽  
Stage Iv Disease ◽  
Oncology Practice ◽  
Practice Methods ◽  
Tumor Types

9546 Background: As the cancer population ages, a brief, comprehensive measure is needed to characterize the “functional age” of a patient, in order to optimize treatment decisions and evaluate outcomes based on factors other than chronological age. A geriatric assessment (GA) evaluates factors other than age that predict morbidity and mortality in older adults. The goals of this study are to describe the results of a GA performed in 500 older adults with cancer from 7 participating institutions and to evaluate the feasibility of completing this assessment in oncology practice. Methods: The GA is comprised of validated measures of functional status, comorbidity, cognition, psychological status, social functioning and support, and nutritional status (Hurria et al, Cancer 2005). The GA was completed prior to the start of a new chemotherapy regimen in patients age ≥ 65 with a solid tumor or lymphoma. Results: 500 patients (mean age 73; range 65–91) completed the GA. The most common tumor types were lung (29%), GI (29%) and breast/gyn (22%) cancer; 57% had stage IV disease. The GA revealed that 41% of patients needed assistance with instrumental activities of daily living despite a mean physician-reported KPS of 85 (range 50–100), 92% had ≥1 comorbid medical conditions (mean 2.5; range 0–9), 95% took ≥ 1 medications (mean 5; range 0–23), 16% had ≥ 1 falls in the past 6 months, 6% had gross cognitive impairment on the Blessed Orientation-Memory-Concentration Test, and 39% had > 5% weight loss in the past 6 months. The mean time to complete the GA was 27 minutes (range 10–80); 94% were satisfied with the GA length and 70% were able to complete the GA without assistance. Multivariate logistic regression identified the following sociodemiographic and disease variables predict the need for assistance with completion of the GA: age ≥ 80 (p=0.02), high school education or less (p<0.01), non-white race (p<0.01), and the presence of metastatic disease (p=0.01). Conclusions: This brief GA is largely self-administered, can be completed by the majority of older patients without assistance, and identifies important deficits and problems that may impact morbidity and mortality. Prospective data are being acquired to identify factors in the GA that predict chemotherapy toxicity in older adults with cancer. No significant financial relationships to disclose.

Genetic background and risk of lung adenocarcinoma in never smokers.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e18549-e18549
Author(s):  
Kazuya Takamochi ◽  
Shiaki Oh ◽  
Kenji Suzuki
Keyword(s):  
Family History ◽  
Lung Adenocarcinoma ◽  
Genetic Background ◽  
Benign Tumor ◽  
Past History ◽  
Lung Cancers ◽  
Multiple Primary ◽  
History Of ◽  
Never Smokers ◽  
Lung Adenocarcinomas

e18549 Background: The causative association between tobacco smoking and lung cancer is well-known. However, the mechanism underlying the pathogenesis of lung adenocarcinoma in never smokers remains unclear. Recently, several driver oncogenes, such as EGFR and EML4-ALK, have been identified in lung adenocarcinomas ofnever smokers. Methods: This was a retrospective review of 596 patients with surgically resected lung adenocarcinomas between February 2009 and October 2012. The clinicopathological factors (age, gender, and pathological stage), EGFR and KRASmutation status, past history of any cancer or benign tumor, family history of any cancer, and the presence of multiple primary lung cancers were compared between never smokers (n = 312) and smokers (n = 284). Results: Lung adenocarcinomas in never smokers were more frequently found in females (P < 0.001) and in patients with early stage disease (P = 0.01) than those in smokers. EGFR mutations were detected in 183 (59%) never smokers and in 89 (31%) smokers (P < 0.001). K-ras mutations were detected in nine (3%) never smokers and in 57 (20%) smokers (P < 0.001). The proportion of patients with a past history of any cancer was higher in smokers than in never smokers (28% vs 21%, P = 0.03). This may reflect the fact that tobacco smoking can cause various types of cancers. In contrast, the proportions of patients with any benign tumor and a family history of any cancer were higher in never smokers than in smokers (14% vs 4%, P < 0.001 and 20% vs 13%, P = 0.02). These findings may suggest that a certain genetic background is involved in the pathogenesis of lung adenocarcinoma in never smokers. The frequency of multiple primary lung cancers was not significantly different between never smokers and smokers (6% vs 5%, P = 0.6). In never smokers, the EGFR and KRASmutation status was not associated with the frequency of a past history of any cancer or benign tumor, a family history of any cancer or the presence of multiple primary lung cancers. Conclusions: A certain genetic predisposition is suspected to be involved in the pathogenesis of lung adenocarcinoma in never smokers. Further studies are thus needed to elucidate the genetic alterations associated with the susceptibility to lung adenocarcinoma in never smokers.

Evolving risk of therapy-related myelodysplastic syndromes and acute myeloid leukemia (tMDS/AML) following modern cancer therapies.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 7516-7516
Author(s):  
Abhay Singh ◽  
Chebli Mrad ◽  
Mark G Faber ◽  
Theresa Hahn ◽  
Eunice S. Wang ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Stage Iv ◽  
Cancer Registries ◽  
Population Based ◽  
Stage I ◽  
Cancer Therapies ◽  
Stage Iv Disease ◽  
Seer Data ◽  
Similar Decrease

7516 Background: Data describing risks of tMDS/AML after targeted and immunotherapy (IO) agents are lacking. Melanoma (Mel) and renal cell carcinoma (RCC) are considered chemotherapy insensitive and have been treated with IO (interferon and interleukin) since the 1990s. In 2004, use of tyrosine kinase inhibitors (TKIs) began in non-small cell lung cancer (NSCLC) and expanded to RCC in 2005 and Mel trials in 2011. Checkpoint inhibitor (CPI) use began in 2011 for Mel, 2012 for NSCLC in trials and later for RCC. For multiple myeloma (MM), use of lenalidomide has been increasing since 2007. All these modern therapies have well described immunomodulatory functions. Methods: Using 17 population-based SEER cancer registries, we studied 565,149 patients diagnosed from 2000-2015 with Mel, RCC, NSCLC, or MM who survived ≥1 year and assessed risk of tMDS/AML across periods P1 (2000-2005), P2 (2006-2010) and P3 (2011-2015). Censoring occurred at 5 years of follow up to limit bias and assess risk alteration across approval and utilization periods of these modern therapies. Results: tMDS/AML risk was significantly elevated after RCC in P1 [standardized incidence ratio (SIR): 1.61, possibly from chemo exposure that was still prevalent to some extent in P1 period] and a downtrend noted in P2 (SIR: 1.11) and P3 (SIR: 0.60). tMDS/AML risk after Mel showed similar downtrend, not statistically significant. In contrast, risk for tMDS/AML after MM increased across all periods ( SIRs 4.51 > 5.05 > 5.23), and risk after NSCLC increased from P1 to P2 but decreased thereafter, pattern most pronounced in stage I-III NSCLC ( 1.64 > 3.15 > 1.92). Conclusions: Periods when TKI and CPI use became standard in Mel and RCC, we observed a decrease in tMDS/AML risk. Similar decrease in the most recent period for stage I-III NSCLC was observed, possibly due to progression of these earlier staged cancers resulting in receipt of TKIs and CPI for stage IV disease. tMDS/AML risk after MM increased contradicting the decline in risk previously reported in the literature. Discordance may be due to survival bias as MM patients are now living longer (SEER 5-yr survival in ‘00 was 35% and 53% in ‘15) with more time to develop tMDS/AML. Overall, aside from better efficacy and/or tolerability of modern therapies, another observed benefit was lower tMDS/AML risk. This risk was lower than general population in Mel/RCC, suggesting a possible protective effect of these therapies. SIR tables/graphs with updated SEER data (available 04/2020) with follow up through 2018 will be presented.

scholarly journals MET Exon 14 Mutations in Non–Small-Cell Lung Cancer Are Associated With Advanced Age and Stage-Dependent MET Genomic Amplification and c-Met Overexpression

2016 ◽  
Vol 34 (7) ◽  
pp. 721-730 ◽  
Author(s):  
Mark M. Awad ◽  
Geoffrey R. Oxnard ◽  
David M. Jackman ◽  
Daniel O. Savukoski ◽  
Dimity Hall ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Molecular Subtype ◽  
Stage Iv ◽  
Small Cell ◽  
Chromosome 7 ◽  
Small Cell Lung ◽  
Genomic Amplification ◽  
Lung Cancers ◽  
Never Smokers ◽  
Egfr Mutant

Purpose Non–small-cell lung cancers (NSCLCs) harboring mutations in MET exon 14 and its flanking introns may respond to c-Met inhibitors. We sought to describe the clinical, pathologic, and genomic characteristics of patients with cancer with MET exon 14 mutations. Patients and Methods We interrogated next-generation sequencing results from 6,376 cancers to identify those harboring MET exon 14 mutations. Clinical characteristics of MET exon 14 mutated NSCLCs were compared with those of NSCLCs with activating mutations in KRAS and EGFR. Co-occurring genomic mutations and copy number alterations were identified. c-Met immunohistochemistry and real-time polymerase chain reaction to detect exon 14 skipping were performed where sufficient tissue was available. Results MET exon 14 mutations were identified in 28 of 933 nonsquamous NSCLCs (3.0%) and were not seen in other cancer types in this study. Patients with MET exon 14–mutated NSCLC were significantly older (median age, 72.5 years) than patients with EGFR-mutant (median age, 61 years; P < .001) or KRAS-mutant NSCLC (median age, 65 years; P < .001). Among patients with MET exon 14 mutations, 68% were women, and 36% were never-smokers. Stage IV MET exon 14–mutated NSCLCs were significantly more likely to have concurrent MET genomic amplification (mean ratio of MET to chromosome 7, 4.3) and strong c-Met immunohistochemical expression (mean H score, 253) than stage IA to IIIB MET exon 14–mutated NSCLCs (mean ratio of MET to chromosome 7, 1.4; P = .007; mean H score, 155; P = .002) and stage IV MET exon 14–wild-type NSCLCs (mean ratio of MET to chromosome 7, 1.2; P < .001; mean H score, 142; P < .001). A patient whose lung cancer harbored a MET exon 14 mutation with concurrent genomic amplification of the mutated MET allele experienced a major partial response to the c-Met inhibitor crizotinib. Conclusion MET exon 14 mutations represent a clinically unique molecular subtype of NSCLC. Prospective clinical trials with c-Met inhibitors will be necessary to validate MET exon 14 mutations as an important therapeutic target in NSCLC.

Treatment exceeds expectations in a patient with non-small cell lung adenocarcinoma with an EGFR exon 20 mutation

2019 ◽  
Vol 26 (1) ◽  
pp. 206-208
Author(s):  
Agnes McAuliffe ◽  
Poorva Bindal ◽  
Meredith Haley ◽  
James Vredenburgh
Keyword(s):  
Tyrosine Kinase ◽  
Lung Adenocarcinoma ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Stage Iv ◽  
Chemotherapeutic Agents ◽  
Small Cell ◽  
Specific Gene ◽  
Small Cell Lung ◽  
Exon 20

Non-small cell lung adenocarcinoma is the most common type of lung cancer but is often difficult to treat. New treatment options have emerged with the class of tyrosine kinase inhibitors, but it has been found that certain genetic mutations in the epidermal growth factor receptor (EGFR) receptor are not as sensitive to this treatment as others. We present a case of a 78-year-old man who was diagnosed with stage IV non-small cell lung adenocarcinoma with an EGFR exon 20 mutations treated with pemetrexed, nivolumab, and then docetaxel. He has lived over four years after his initial diagnosis. This case illustrates the importance of genetic testing of patients to evaluate for specific gene mutations. It highlights the fact that these patients with exon 20 mutations are not sensitive to tyrosine kinase inhibitor treatment and often respond better to chemotherapeutic agents.

scholarly journals Toxicity with small molecule and immunotherapy combinations in non-small cell lung cancer

2020 ◽  
Author(s):  
H. Adderley ◽  
F. H. Blackhall ◽  
C. R. Lindsay
Keyword(s):  
Small Molecule ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Growth Factor Receptor ◽  
Stage Iv ◽  
Stage Iii ◽  
Driver Mutations ◽  
Anaplastic Lymphoma ◽  
Significant Toxicity ◽  
Stage Iv Disease

Abstract Treatment stratification in stage IV NSCLC is guided by identification of oncogene driver mutations. Actionable mutations with current licenced therapeutic agents include epidermal growth factor receptor (EGFR), rearrangements of anaplastic lymphoma kinase (ALK), ROS-1 and BRAF V600. Alongside progress with small molecule therapy, developments in immune checkpoint inhibitors (CPIs) have transformed the landscape of stage III and stage IV NSCLC. The success of CPIs has led to evaluation with small molecule therapy in both concurrent and sequential settings. In this review we summarise recent results of combination CPIs and tyrosine kinase inhibitors (TKIs) in stage IV NSCLC, detailing significant toxicity and its potential mechanisms with both concurrent and sequential approaches. As more therapeutic targets are being discovered it is becoming increasingly important for clinicians to correctly sequence therapy for delivery of safe and effective treatment. In addition to stage IV disease we suggest that comprehensive molecular profiling of key NSCLC drivers, particularly in stage III disease, will help to inform optimal treatment sequencing and minimise potential toxicity.

Lorlatinib for advanced ALK and ROS1+ non-small cell lung cancer (NSCLC): Efficacy and treatment sequences in the IFCT-1803 LORLATU expanded access program (EAP) cohort.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9615-9615
Author(s):  
Simon Baldacci ◽  
Virginie Avrillon ◽  
Benjamin Besse ◽  
Bertrand Mennecier ◽  
Michael Duruisseaux ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Real Life ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Published Data ◽  
Brain Radiotherapy ◽  
Stage Iv Disease ◽  
Major Treatment ◽  
Never Smokers ◽  
Treatment Sequences

9615 Background: Lorlatinib, a third-generation tyrosine kinase inhibitor targeting ALK and ROS1, has been made available in France starting October 2015 through an EAP for advanced, refractory, ALK+ NSCLC after the failure of chemotherapy and TKIs. Besides the landmark, multi-cohort phase II trial that assessed lorlatinib in ALK+ NSCLC, real-life evidence regarding the efficacy and safety, as well as treatment sequences including lorlatinib, is lacking. Methods: We report the cohort of consecutive patients with advanced, refractory, ALK or ROS1+ NSCLC enrolled in the French EAP of lorlatinib from October 2015 to October 2019. Data were collected from medical records by French Cooperative Thoracic Intergroup (IFCT) research study assistants on site. Primary endpoint was progression-free survival. Results: 200 patients were included: 143 (71.5%) ALK+, 57 (28.5%) ROS1+, 87 (44%) men, 127 (66%) never-smokers, and 167 (85%) stage IV disease. Mean age was 59 years. At the time of initiation of lorlatinib, 146 (74%) patients had Central Nervous System (CNS) disease (78 % for ALK+, 63% for ROS1+), 131 (76%) were PS 0/1. Lorlatinib was delivered as 2nd/3rd/4th/5th+ line in 3%/17%/27%/53%of ALK+ patients and in 30%/30%/16%/24%of ROS1+ patients, respectively. 150 (75%), 185 (93%), 138 (69%), and 80 (40%) patients had received prior chemotherapy, crizotinib, 2nd generation TKIs, and brain radiotherapy, respectively. Median PFS and OS from the initiation of lorlatinib were 11.8 (95% CI 7.3-14.6) months and NR (95% CI 18.6-NR) months, respectively for ALK+ patients and 7.6 (95% CI 6.2-10.2) months and 20.9 (95% CI 10.0-NR) months, respectively for ROS1+ patients. ORR and DCR were 46.2% (95% CI 37.6-54.7) and 86.2% (95% CI 80.2-92.1), respectively for ALK+ patients and 47.1% (95% CI 33.4-60.8) and 88.2% (95% CI 79.4-97.1), respectively for ROS1+ patients. CNS ORR was 41.7% (95% CI 33.3-50.1) and 37.7% (95% CI 24.7-50.8), respectively. With a median follow-up of 15.6 (95% CI 14.0-17.6) months, progression under lorlatinib treatment was observed in 71 (50%) ALK+ patients and 35 (61%) ROS1+ patients, and CNS progression in 24 (34%) and 8 (23%) patients, respectively. The safety profile of lorlatinib was consistent with published data. Conclusions: These real-life results confirmed lorlatinib as a major treatment option for patients with advanced refractory ALK or ROS1+ NSCLC.

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