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R. Perez-Soler
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ED 11 - Extending Personalized Treatment Beyond EGFR (ID 11)
- Event: WCLC 2015
- Type: Education Session
- Track: Community Practice
- Presentations: 4
- Moderators:R. Perez-Soler, R. Camidge
- Coordinates: 9/09/2015, 14:15 - 15:45, 401-404
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ED11.01 - What Testing Is Needed for Clinical Treatment? (ID 1814)
14:15 - 15:45 | Author(s): P.A. Bunn, Jr
- Abstract
- Presentation
Abstract:
The current IASLC/CAP/AMP guidelines indicate that testing for EGFR mutations and ALK fusions is recommended before instituting therapy in patients with advanced lung cancers with adenocarcinoma features. The guidelines indicate that the guidelines would be updated as other therapies become available for specific drivers. Since these guidelines were published, considerable information has become available on molecular changes that cause resistance to the first generation EGFR and ALK tyrosine kinase inhibitors (TKIs) and new 2nd and 3rd generation drugs to treat molecular resistance are in the clinic are likely to be approved in 2015. New drugs are also in development for other molecular drivers that have been reported in lung cancer including fusions that activate ROS1, RET, NTRK, and FGFR; mutations that activate KRAS, BRAF,HER2, and FGFR; and amplifications that activate MET, FGFR and HER2. It is also likely that some of these agents will approved in the near future. These developments bring into focus the most appropriate methods to test for molecular drivers in lung cancer. The techniques include direct sequencing, PCR testing for mutation hot spots, Next generation whole exome sequencing for mutations, translocations and amplifications, immunohistochemical testing for activated proteins or specific mutations, FISH testing for specific translocations, fusions, and amplifications. The sequential testing of one gene at a time is very inefficient especially with respect to the time it takes to complete testing, with the total cost and with respect to the amount of tissue necessary to complete the testing. Thus, multiplex testing is becoming far more common. However, in the US, the FDA’s companion diagnostic tests are one a time for specific tests for specific drugs. This one off policy is threatening the ability to perform one test for multiple analytes simultaneously. Hopefully, these issues can be resolved in the near future. What are the molecular changes that appear to be drivers for which there exist therapeutic TKIs? We can first discuss the development of resistance to 1st generation EGFR and ALK TKIs. About half of all patients who progress on a 1st generation EGFR TKI will have a secondary gatekeeper mutation, T790M that limits binding of 1st generation EGFR TKIs to the EGF receptor. 3rd generation EGFR TKIs such as AZD9291 and CO1686 (rocelitinib) have been shown to produce objective clinical responses in about 60% of patients with T790M who progress on a first generation EGFR TKI. These responses are associated with a median PFS of about 10 months. These drugs bind irreversibly to the T790M receptor and to activating mutations such as del19 and L858R but do not bind to the wildtype receptor. Therefore they have far less skin rash and diarrhea compared to the 1st generation inhibitors. Rocelitinb may cause hyperglycemia in up to a third of patients that is believed to be caused by a metabolite that inhibits IGFR. The use of oral anti-hyperglycemic agents such as metformin may be required for glucose control in these patients. Rocelitinib may also cause prolongation of the QTc on EKGs and thus monitoring is required. This side effect is rare but requires monitoring. AZD9291 may be associated with slightly more skin rash and diarrhea and uncommon reports of pneumonitis have been reported. The mechanism of resistance to these agents is under investigation but most often appears to be activation of alternative signaling pathways or phenotypic switching to a mesenchymal state. There are multiple tests available to detect the T790M mutation and many studies are evaluating its presence in circulating free DNA. Such analyses seem to be quite specific but less sensitive to analyses of tumor tissue. Testing for mutations in circulating free DNA is quite appealing because it does not require another tumor biopsy. Crizotinib which was the first agent approved for ALK positive cases, is also a potent ROS1 and MET inhibitor. ROS1 may be activated by fusion to other genes on the same chromosome and detected by FISH or Next generation sequencing. Crizotinib has been reported to produce objective response is about 60% of cases with ROS1 fusions with median progression free survival of about 16 months. Crizotinib has also been reported to produce objective responses in about 2/3 of patients with high MET amplification although the number of patients studied is very low. Additional studies are ongoing. Because MET amplification is frequent in patients who progress on 1st generation EGFR TKIs that do not have T790M, MET inhibitors are also being studied on this setting. Both ceritinb and alectinib have been approved for patients with ALK fusions who have progressed on crizotinib. It is clear that the two drugs have different activity among various resistance mutations for ALK. Thus, rebiopsy of tumor or testing of circulation free DNA may become standard in patients progressing on ALK TKIs as it is in patients progressing on EGFR TKIs. BRAF mutations occur in about 2% of advanced NSCLC patients and the V600E mutation is the most common. BRAF TKIs such as vemurafinib have been reported to produce frequent responses in NSCLC patients with V600E BRAF mutations. In melanoma the combination of BRAF inhibitors with MEK inhibitors has been more effective than BRAF inhibitors alone and this combination is being studied in NSCLC patient with BRAF mutations. HER 2 may be activated by either mutation or amplifications and the response to various HER inhibitors may vary by the method of activation. About 2% of patients have activation by amplification and about 2% by mutation (usually exon 20 insertions). The irreversible pan HER TKIs such as neratinib, afatinib and dacomitinib have not produced high response rates in these patients. However a phase 1 trial of the combination of niratinib with temsirolimus produced higher responses in both breast and lung cancers and a phase 2 study of the combination in lung cancers with HER2 mutations/amplifications is in progress. Other HER2 inhibitors have been reported to produce occasional responses but we await formal study of such agents. RET and NTRK fusions have been reported I about 1% of patients and there are sporadic reports of responses to specific TKIS. Formal studies are in progress but may not be reported for some time due to the rarity of the abnormalities and the fact that multiple TKIs are available. FGFR may be activated by amplification, fusion and mutations and there are both quite specific FGFR TKIs and multi-TKIs that have been studied in small numbers of patients. It is fair to say that response rates to specific FGFR TKIs are low in patients with squamous cell carcinoma patients with FGFR amplification. Additional studies with other biomarkers and other agents are ongoing. The most frequent oncogenic driver in lung cancer is KRAS. No specific TKI has been developed. Downstream inhibitors such as MEK inhibitors and FAK inhibitors have the most study to date. Response rates as single agents are relatively low and combination studies are in progress. In summary, the increased numbers of TKIs specific for various molecular drivers in lung cancer is becoming far more important not only a diagnosis but also at the time of progression. Future studies will focus on multiplex testing and testing of circulating free DNA.
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ED11.02 - Communicating with Pathologists About Molecular Testing (ID 1815)
14:15 - 15:45 | Author(s): C.O. Lara-Torres
- Abstract
- Presentation
Abstract:
Technologic and scientific development in medicine and the biomedical sciences has led to almost immediate transfer of knowledge and methodology applied initially in the research lab to the clinic, producing a profound impact in screening, diagnosis and treatment. These enormous amount of information and specialized skills in the medical practice have made it necessary to integrate multidisciplinary teams to improve quality of cancer care.Lung cancer is the most common neoplasia worldwide as well as the leading cause of cancer-related death, with more than 50% of patients presenting with stage IV disease at diagnosis (1). Therefore, lung cancer management usually requires the collaboration of surgeons, medical oncologists, radiation oncologists, pathologists, nurses, and other health care professionals (2). Given the fact that many patients will present with locally advanced or metastatic disease, only small amounts of tissue or cell preparations will be available for morphologic analysis, immunohistochemistry and molecular testing. Recommendations from academic centers and agencies are in favor of limiting the amount of immunohistochemical stains in order to save tissue for molecular assays, stressing the need to integrate pathologist to multidisciplinary teams, where clinical information is exchanged, and specific differential diagnosis and objectives established in a case-to-case basis (3). The traditional role of pathologist in lung cancer has been to establish histological diagnosis of malignancy, as well as proper taxonomic allocation according to widely accepted classification schemes. (4) This approach sets pathologist within single moment interventions early in the course of patient management, aside from opportunities to collaborate during the rest of care. However, the advent of personalized medicine, characterized by the identification of biological features in cells that predict benefit from specific targeted drugs, opened up the way for pathologist to actively participate with the team in the selection of treatment and patient follow-up. Overall, from 60-70% of NSCLC have specific mutations of well characterized oncogenic drivers, some of them with 1st line treatment drugs and many with targeted therapies under development. Current guidelines of advance stage disease recommend initial characterization of EGFR mutation status and ALK rearrangement, although there is building evidence to support testing of a number of actionable genes such as HER2, BRAF, MET, RET, ROS1, or other biomarkers with predictive capacity such as microsatellite instability (5). Multiple methods and technological platforms have been developed to identify gene mutations, and although most of them have very high specificity values, the sensitivity to detect a mutant clone from a background of wild type DNA is wide. Conventional Sanger sequencing will identify a mutation if it is present in 10-20% of the sampled cells, pyrosequencing increases the level to 1%, mutant-enriched polymerase chain reaction (PNA-LNA PCR, ARMS, etc.) can detect a mutant gene among as many as 10[3] wild-type alleles (0.1-1%) with comparative performance to next generation sequencing(6). These differences in analytical sensitivity do not only affect the number of EGFR mutated cases identified, but may also impact the clinical results obtained when using TKI therapy. For example, studies suggest that high EGFR mutation allele burden at diagnosis may be associated with increased progression-free survival and overall survival in patients treated with tyrosine kinase inhibitors, based in sensitivity differences between conventional sequencing and allele-specific PCR(7,8). In the light of these challenges, pathologist face the need to secure tissue availability and adequacy for testing in order to increase the diagnostic yield of molecular characterization. This demands the establishment of changes in sample management and processing, depending on the biological material to be tested. For example, rapid on-site evaluation may be performed in cytological specimens from fine needle aspirates. In the case of CT-guided transthoracic biopsies, one initial core may be submitted for frozen section or studied with cytological imprints to assess tumor viability. If proper cellular material is identified, this core may be entirely used for molecular testing and subsequent cores destined for histological processing. Once the tissue is paraffin-blocked, the tissue cuttings product of facing the block may be saved in a sterile, DNAase/RNAase-free tube for later use if necessary. It is established that patients will ultimately develop resistance to targeted therapies through different mechanisms, either the emergence of mutations in the target gene or the acquisition of mutations or over-expression of oncogenes that overcome this inhibition. Studies have proved that at tumor progression, a number of cases may have a morphological switch from adenocarcinoma to sarcomatoid carcinoma or small-cell carcinoma (9), requiring therapy adjustments. Re-biopsy allows molecular evaluation as well as morphologic analysis, however; it is an invasive procedure that not all patients may undergo. Alternative highly sensitive molecular methods may be used for patient follow-up without the need of invasive interventions. Blood sample-based PCR or NGS can detect circulating free DNA from the tumour (liquid biopsy), the concordance rate between tissue and plasma for EGFR mutation going from 58.3% to 93.1%, stressing the need of analytical improvement. Of especial interest is the fact that when examining the appearance of the T790M mutation in serial blood samples, this mutation could be detected in the plasma DNA before clinically evident disease progression. (10) NSCLC diagnostics is rapidly changing to combine a dual morphologic-molecular approach, where initial HE-slide examination is used to confirm malignancy and to allocate the tissue sample to a group of molecular test relevant to the cellular composition of the tumour. Continuous increase in the number of genes responsible of oncogenesis in lung carcinoma ensures the development of new targeted drugs as well as active communication from all the members of the multidisciplinary team. References 1) Aisner DL, Marshall CB. Molecular pathology of non-small cell lung cancer: a practical guide.Am J Clin Pathol. 2012 Sep;138(3):332-46. 2) Pan CC, Kung PT, et al. Effects of Multidisciplinary team care on the survival of patients with different stages of Non-Small Cell Lung Cancer: A National Cohort study. PLoS One. 2015 May 12;10(5):e0126547. 3) Lindeman NI, Cagle PT, Beasley MB, et al: Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: Guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med 137:828-860, 2013 4) Cagle PT, Myers J.Precision medicine for lung cancer: role of the surgical pathologist. Arch Pathol Lab Med. 2012 Oct;136(10):1186-9. 5) Dacic S, Nikiforova MN.Present and future molecular testing of lung carcinoma. Adv Anat Pathol. 2014 Mar;21(2):94-9. 6) Young EC, Owens MM, Adebiyi I, et al. A comparison of methods for EGFR mutation testing in non-small cell lung cancer. Diagn Mol Pathol. 2013 Dec;22(4):190-5. 7) Kim HS, Sung JS, Yang SJ. Predictive efficacy of low burden EGFR mutation detected by next-generation sequencing on response to EGFR tyrosine kinase inhibitors in non-small-cell lung carcinoma. PLoS One. 2013 Dec 20;8(12):e81975. 8) Zhou Q, Zhang XC, Chen ZH. Relative abundance of EGFR mutations predicts benefit from gefitinib treatment for advanced non-small-cell lung cancer. J Clin Oncol. 2011 Aug 20;29(24):3316-21. 9) Sequist LV, Waltman BA, Dias-Santagata D. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011 Mar 23;3(75):75ra26. 10) Sorensen BS, Wu L, Wei W, et al. Monitoring of epidermal growth factor receptor tyrosine kinase inhibitor-sensitizing and resistance mutations in the plasma DNA of patients with advanced non-small cell lung cancer during treatment with erlotinib. Cancer. 2014 Dec 15;120(24):3896-901.
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ED11.03 - 1st Line and Beyond for ALK, ROS-1, BRAF, RET, FGFR Positive Lung Cancer (ID 1816)
14:15 - 15:45 | Author(s): D.R. Spigel
- Abstract
Abstract:
Remarkable progress has been made in the treatment of ALK-rearranged NSCLC with the initial approval of crizotinib. Multiple next-generation agents are impacting care as approved therapies in some regions of the world or in first- and second+-line clinical trials where early data are promising. Additional development of crizotinib and newer agents in ROS-1-positive NSCLC is quickly changing how patients are evaluated at diagnosis. Moreover, maturing data in BRAF-mutated NSCLC with BRAF and MEK inhibitors, along with early data in RET- and FGFR-positive NSCLC support broader and earlier testing in the care of patients with advanced NSCLC. The data for, and challenges of, selecting the best first-line (and beyond) options for patients with ALK, ROS-1, BRAF, RET, FGFR, or other altered NSCLC will be reviewed.
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ED11.04 - Prioritizing New Agents When More than One Is Available and Combining Targeted Agents (ID 1817)
14:15 - 15:45 | Author(s): R. Camidge
- Abstract
- Presentation
Abstract:
When more than one drug exists for the same target (e.g. erlotinib, icotinib, gefitinib and afatinib for EGFR mutant NSCLC), decisions in terms of which drug to commence targeted therapy with may be based on personal experience, side effects and cost. Until head-to-head trials in the same sensitive target population read out, any potential efficacy differences remain speculative. Other than to switch out drugs based on tolerability issues, the anti-cancer benefit from sequential use of different drugs in the same class/generation as a strategy separate from any benefit of ongoing target suppression post-progression with the same drug also remains largely unproven. However, as new generation drugs are developed, drugs directed against the same dominant driver now exist which have activity against both the initial form of the target and common acquired resistance forms (e.g. ceritinib and alectinib for ALK+ NSCLC, or rociletinib and AZD9291 for EGFR mutant NSCLC). While initial licensing strategies have focused on sequential use of such drugs after first generation drugs, studies are also underway looking to see if first line use of these next generation drugs could be more beneficial in the relevant molecularly selected population. As mechanisms of acquired resistance become better understood, specific actionable second drivers, co-existing with the initial sensitive form of the oncogenic driver, are now being identified (e.g. MET amplification with EGFR mutations). Preclinically, inhibition of both drivers is required to achieve cancer control in this setting. Clinically, trials of combination therapy are showing promise with determination of the exact predictive cutpoint in continuous variables such as MET emerging as a key issue. With more extensive molecular testing being deployed upfront, rather than in tiered testing strategies and separate from in the acquired resistance setting, multiple potential molecular drivers on each patient are now being reported to treating physicians. When some of these are known acquired mechanisms of resistance (e.g. MET or T790M in EGFR mutant), concern may arise re whether initial therapy will be effective. However, most diagnostic assays do not give information on the proportion of each molecular aberration. Consequently, a highly sensitive test can detect a small clonal fraction of a resistance mechanism that will later be selected out by use of the initial targeted therapy, but does not preclude an initial response. In contrast, germline abnormalities present in all cells, such as can occur with T790M, would preclude an initial response to the relevant targeted therapy. As such germline events are very rare, initial use of a targeted agent still makes most sense. While defined oncogenic drivers are often perceived to be mutually exclusive (e.g. EGFR and ALK), exceptions do occur. While there appears to be no specific growth advantage to having two oncogenic drivers in the same cell in the absence of a specific selection pressure, such examples of double drivers could reflect false positives, true positives where one of them is somehow non-functional (e.g. an ALK rearrangement detected by FISH, which is not transcribed), or true positives where each is present in a different cell population. Again, as proportional positivity is not a feature of most diagnostic assays, starting with monotherapy for the abnormality that is either easiest to target or has the lowest chance of being non-functional (e.g. a point mutation over a chromosomal abnormality), makes the most clinical sense. At acquired resistance, rebiopsy and reanalysis for changes in biology including the dominance of the other initial driver should be strongly considered. Perhaps the biggest challenge has been the proliferation of multiplex reports detailing a range of abnormalities in the same cancer, where the exact driver status and biological significance of the abnormalities remains unclear. Caution should be exercised in assuming that all changes are true drivers and extreme caution should be exercised if attempting to combine available targeted drugs that have not been combined before in the absence of a formal phase I study.
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MINI 05 - EGFR Mutant Lung Cancer 1 (ID 103)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 14
- Moderators:Y. Yatabe, R. Perez-Soler
- Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 2a-3b
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- Abstract
- Presentation
Background:
As epidermal growth factor receptor (EGFR) mutation a strong predictor of EGFR tyrosine kinase inhibitor (TKI) responsiveness, there are still around 10% TKI-naïve patients early refractory to first line TKIs. We aimed to find clinical predictors of TKIs responsiveness in EGFR-mutant non-small cell lung cancer (NSCLC) patients and create a scoring system as progression free survival (PFS) prediction.
Methods:
This retrospective study evaluated 262 patients harboring EGFR mutation received TKIs as first line therapy for NSCLC between January 2011 and December 2013. Patients were assigned to test (N=131) and validation (N=131) by time sequence. Patients with age ≤ 40, uncommon EGFR mutation, poor performance status, more sites of distal metastasis, and lymphocyte to monocyte ratio ≤3 were independently associated with poor progression free survival. These five factors were included in the scoring system and 3 predictive groups were formed by total score. Table. 1 Univariate and Cox regression analysis of progression free survivalUnivariate analysis Multivariate analysis PFS (M) P value P value Age >40 ≤40 11.6 3.3 0.001 0.002 BMI >24 ≤24 14.9 9.1 0.027 0.928 Gender Male Female 9.3 12.0 0.292 DM YES NO 9.1 11.5 0.500 Smoking Never Former / current 11.5 7.6 0.413 Performance status ECOG 0-2 ECOG 3-4 11.5 2.7 0.009 0.012 Mutation Common Uncommon 11.5 4.1 <0.001 <0.001 Tumor type Adenocarcinoma Non-adenocarcinoma 11.1 9.8 0.789 No. of distal metastasis 0 1-2 >2 21.4 11.3 6.1 <0.001 <0.001 0.015 <0.001 Malignant effusion Yes No 9.1 11.6 0.031 0.946 Lymphocyte to monocyte ratio >3 ≤3 13.4 7.4 <0.001 0.047
Results:
Progression free survival in the test group were 15.7 months(m) for 0-1 points, 9.3 m for 2 points, 4.0 m for 3-6 points (p <0.001). In the validation test, Progression free survival in there predictive groups each were 13.7 m, 9.5 m, 4.8 m (p <0.001). Between the test and validation groups, no significant differences were found in each one of the three predictive groups. Figure 1
Conclusion:
The score appears valid and reproducible. It can stratify NSCLC patients harboring EGFR mutation using first line EGFR-TKIs into long, intermediate and short PFS groups.
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- Abstract
- Presentation
Background:
ATP binding cassette superfamily G member 2 (ABCG2) has been demonstrated to be associated with the effect of chemotherapy/targeted therapy in non-small-cell lung cancer (NSCLC) and the single nucleotide polymorphisms (SNPs) of ABCG2 gene are supposed to affect the expression of ABCG2 protein. The purpose of this study was to investigate the correlation between SNPs of ABCG2 and outcome of tyrosine kinase inhibitions (TKIs) therapy in Chinese advanced NSCLC patients.
Methods:
SNP genotyping(34 G/A, 421 C/A, 1143 C/T and -15622 C/T)of ABCG2 gene in 100 patients was performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The clinical characteristics of 100 patients were collected. A total of 70 patients were treated with TKIs(gefitinib, erlotinib and icotinib). The association between ABCG2 polymorphisms and clinical characteristics was evaluated. Kaplan-Meier survival curves were plotted for overall survival (OS) and analyzed with the log-rank test. Cox proportional hazards model was applied to evaluate the association between OS and clinical or genomic characteristics and estimated the adjusted HR and its 95 %CI.
Results:
The three polymorphisms of the ABCG2 34 G/A, 421 C/A and 1143 C/T occurred more frequently compared with -15622 C/T in Chinese advanced NSCLC patients. The allele A of 421C>A happened frequently in EGFR mutation positive patients (33.3% vs 9.1%, P=0.038). There was no association between ABCG2 polymorphisms and other clinical characteristics (p> 0.05).The median OS of patients with 34G>A mutant type (GA+AA) was 31.0 (95%CI: 22.9-39.1) months , which was significantly longer than those with wild type (GG) , 18.0 (95%CI: 14.9-21.1) months (p=0.005). No significant difference of OS was found in 421 C/A and 1143 C/T polymorphisms (p> 0.05).
Conclusion:
Our findings demonstrate a strong association between the ABCG2 34G>A polymorphism and the overall survival of NSCLC patients treated with TKI. It may be a possible predictor of the clinical outcome of TKIs therapy in NSCLC patients.
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MINI05.03 - P53 Disruptive Mutation Is a Negative Predictive Factor in EGFR M+ NSCLC Treated with TKI (ID 903)
16:45 - 18:15 | Author(s): A.C. Lueers, N. Neemann, R. Prenzel, D. Scriba, K. Wilborn, U. Stropiep, M. Falk, C. Hallas, M. Tiemann, F. Griesinger
- Abstract
- Presentation
Background:
p53 mutations are common in lung cancer, and have also been described in EGFR mutated patients. The impact of p53 mutations in EGFR M+ patients is controversial, especially if classified as “disruptive” and “non-disruptive” according to their functional effect on the p53 protein as proposed by Poeta and colleagues. The aim of the study was therefore to systematically analyze EGFR and p53 mutations within a cohort of patients with lung cancer stage IV (UICC 7), to correlate alterations with clinical characteristics and to investigate a potential impact of p53 mutations on treatment outcome.
Methods:
267 patients from a single center diagnosed with lung cancer stage IV were studied for the presence of EGFR as well as inactivating p53 mutations. Methods for the detection of EGFR mutations included Sanger Sequencing and hybridization based COBAS testing. P53 mutations were detected by Sanger Sequencing. Clinical characteristics including smoking status were available for all patients.
Results:
267 consecutive patients at the lung cancer center of the Pius-Hospital Oldenburg were studied. The overall EGFR mutation rate was 19% (51/267) in all patients, 80% (41/51) showing common mutations of exon 19 or 21. P53 disruptive mutation showed in 16% (8/51) and p53 nondisruptive mutation occurred in 11% (22/51) whereas p53 WT was found in 47% (24/51). In 8/51 (16%) patients p53 analysis was not successful. OS was 37 months in p53 disruptive mutation and p53 WT patients compared to 19 months in p53 nondisruptive mutation (p<0,05). PFS on 1st line TKI therapy was 18 months in p53 nondisruptive mutation and p53 WT patients and 6 months in p53 disruptive mutation (p<0,024). Similar results could be shown in the EGFR common mutation subgroup but not in the uncommon mutation subgroup.
Conclusion:
Significant differences in PFS and OS in EGFR M+ patients were observed depending on p53 mutation status. P53 mutational status is only predictive when disruptive and non-disruptive P53 mutations are differentiated. P53 should be tested prospectively in EGFR M+ patients as management of patients on 1st line TKI may be different.
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- Abstract
- Presentation
Background:
Mutations in the epidermal growth factor receptor (EGFR) are associated with a marked therapeutic response to EGFR-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC). However, clinical predictors of the survival benefit of EGFR-TKI treatment in NSCLC with EGFR activating mutations have not been well elucidated. Therefore, this study evaluated clinical predictors of survival outcome in patients with EGFR mutant NSCLC who were treated with EGFR-TKIs. Mutations in the epidermal growth factor receptor (EGFR) are associated with a marked therapeutic response to EGFR-tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC). However, clinical predictors of the survival benefit of EGFR-TKI treatment in NSCLC with EGFR activating mutations have not been well elucidated. Therefore, this study evaluated clinical predictors of survival outcome in patients with EGFR mutant NSCLC who were treated with EGFR-TKIs.
Methods:
A total of 224 patients with EGFR-mutant lung adenocarcinomas that were treated with EGFR-TKIs were retrospectively reviewed. Treatment outcomes were evaluated based on clinical factors, number of metastasis site and progression patterns.
Results:
The clinical factors associated with reduced progression-free survival (PFS) and overall survival (OS) by univariate analysis were ECOG performance status (PS) ≥ 2, intra- and extrathoracic metastasis, presence of extrathoracic metastasis, high number of metastasis sites, metastasis to liver or adrenal gland at baseline, and rapid progression of primary tumor at the time of progressive disease (PD). In multivariate analysis, factors that remained significantly associated with shorter PFS were ECOG PS ≥ 2 (Odds ratio [OR] 2.189 [95% CI, 1.374 – 3.437]; P < 0.001) and rapid progression of primary tumor at PD (OR 1.800 [95% CI, 1.059 – 3.058]; P = 0.030).
Conclusion:
Thus, tumor burden, expressed as the number of metastasis sites at the time of EGFR-TKI treatment, and rapid progression of primary tumor at PD are predictive of inferior survival in patients with lung adenocarcinoma with activating EGFR mutations.
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MINI05.05 - Discussant for MINI05.01, MINI05.02, MINI05.03, MINI05.04 (ID 3531)
16:45 - 18:15 | Author(s): F. Cappuzzo
- Abstract
- Presentation
Abstract not provided
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MINI05.06 - A Phase Ib/II Study of Afainib plus Nimotuzumab in Non-Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib (ID 667)
16:45 - 18:15 | Author(s): J.Y. Lee, S.H. Lim, H. Kim, K.H. Yoo, K.S. Jung, H. Song, M. Kwak, M. Han, J. Sun, S. Lee, J.S. Ahn, K. Park, M. Ahn
- Abstract
- Presentation
Background:
Afatinib (A) is a potent irreversible EGFR TKI and nimotuzumab (N) is a humanized anti-EGFR mAb. In this phase Ib/II study, we aimed to assess the safety and activity of A plus N in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib.
Methods:
Major inclusion criteria were advanced NSCLC with activating EGFR mutation or disease control for at least six months with previous gefitinib or erlotinib therapy. In the phase Ib study using classic 3+3 dose escalation method, patients were treated with A 40mg/d or 30mg/d in combination with N 100mg/w or 200mg/w. One cycle was composed of 4 weeks of treatment. In the phase II study, patients were treated with A plus N in the level of RP2D defined in the phase Ib study.
Results:
Overall, fifty pts were enrolled and treated: 13 in phase Ib and 37 in phase II. At the starting dose level (A 40mg/d + N 100mg/w), one out of 6 pts experienced end-of-cycle 1 DLT (G3 diarrhea), and the dose was up to the next level of A 40mg/d + N 200mg/w. Out of 6 pts at this level, 2 pts experienced DLTs (G3 diarrhea and G3 neutropenia, respectively), and RP2D was accordingly determined as A 40mg/d + N 100mg/w. In the whole treatment duration of the phase II, there was no treatment related death and 10 pts (20%) experienced any grade 3 adverse event, including diarrhea and skin rash. Out of evaluable 50 pts in the phase Ib/II study, the response rate was 36% (18 achieved partial response out of 50) and the median PFS was 4.4 months (95% CI:3.2-5.5 months).
Conclusion:
A and N showed an acceptable safety profile and promising antitumor activity in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib.
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- Abstract
- Presentation
Background:
Targeted therapies have considerably improved the prognosis of patients with non-small cell lung cancer (NSCLC).Although not precision enough, RESIST criteria was still the most often used response assessment method to reflecting the clinical benefits. We propose a non-invasive, folate receptor (FR)–based circulating tumor cell (CTC) detection approach to interpret treatment response of targeted therapy between baseline and follow-up CTC values in EGFR mutation/ALK translocation advanced NSCLC.
Methods:
One hundred and thirty eight patients were enrolled in our study. Peripheral blood was analyzed for CTCs enumeration on negative enrichment by immunomagnetic beads. Changes of CTCs levels were correlated with radiological response. Sequential analyses were conducted to monitor CTC signals during therapy and correlate radiological effects with treatment outcome.
Results:
CTCs were detected (≥8.7CTC) in 84.8% of patients. Pretreatment and pro-treatment blood samples from all 118 EGFR-mutant (19deltion:56, L858R:57, G719x:3, L861Q:1, 19 deletion + L858R:1), 14 ALK translocation lung cancer patients and 6 EGFR wild type patients were collected. Of 89 eligible and evaluable patients, baseline CTC counts were not associated with response to treatment by RECIST (P=0.353). There is no difference between exon 19 deletion and L858R of baseline CTC values. (19deletion:19.4 CTCs, L858R:20.9 CTCs,P=0.222) The change of CTCs values increased correlation with radiological response (P=0.042) after treatment of targeted therapy. There is no significant difference between exon 19 deletion and L858R of CTCs values pre and pro EGFR-TKI treatment.(3.32 vs.12.1, P=0.783)
Conclusion:
This study confirms the predictive significance of CTCs in patients with EGFR mutation/ALK translocation NSCLC receiving targeted therapy. The change of CTCs value correlated significantly with radiological response. This strategy may enable non-invasive, specific biomarker assessment method for using CTC decreases as an early indication of response to targeted therapy and monitoring in patients undergoing targeted cancer therapies.
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MINI05.08 - Comparison of the Efficacy of Dacomitinib v Erlotinib for NSCLC Pts with Del 19/L858R (ID 775)
16:45 - 18:15 | Author(s): S.S. Ramalingam, K.J. O'Byrne, T. Mok, M. Boyer, P.A. Jänne, Z. Goldberg, C.B. Mather, I. Taylor, H. Zhang, L. Paz-Ares
- Abstract
- Presentation
Background:
To date there have been limited randomized comparisons of EGFR tyrosine kinase inhibitors (TKI) in EGFR mutant NSCLC. Dacomitinib is a potent, irreversible EGFR inhibitor that demonstrated robust activity in a phase 2 study for patients with common activating EGFR mutations. Additionally, preclinical data suggests greater activity in patients with common EGFR activating mutations in exon 19 or 21. ARCHER 1009 (NCT01360554) and A7471028 (NCT00769067) each compared the clinical activity of dacomitinib (D) versus erlotinib (E) in advanced NSCLC including patients with common activating EGFR mutations; pooled results are presented.
Methods:
Patients (pts) with locally advanced/metastatic NSCLC were randomized following progression with 1 or 2 prior chemotherapy regimens to treatment with dacomitinib (D) (45 mg PO QD) or erlotinib (E) (150 mg PO QD). The Phase 2 study (A7471028) was open label while the Phase 3 ARCHER 1009 study was double-blind and double dummy. Archived tumor tissue, ECOG performance status (PS) of 0-2, adequate organ function and informed consent were required. Results of the two studies were previously reported individually. Analyses were performed by pooling patients with common EGFR activating mutations from both studies to compare efficacy of D versus E.
Results:
121 patients with any EGFR mutation were enrolled into the two studies with 1 patient randomized but not treated; 101 (53 on D) pts had activating mutations in exon 19 or 21. For patients with exon19/21 mutations, the median PFS was 14.6 months (95%CI 9.0–18.2) for D and 9.6 months (95%CI 7.4–12.7) for E and unstratified HR 0.717 (95%CI 0.458–1.124) with 1-sided p=0.073. The median OS was 26.6 months (95%CI 21.6–41.5) for D and 23.2 months (95%CI 16.0–31.8) for E and unstratified HR 0.737 (95%CI 0.431–1.259) with 1-sided p=0.132. The corresponding pooled analyses were conducted separately in exon 19 and exon 21. The adverse-event profile did not differ between the activating mutation subset and the overall population. Figure 1
Conclusion:
Dacomitinib may be associated with an improved PFS and OS compared to Erlotinib in patients with exon 19/21 EGFR mutations. A prospective P3 study comparing D to another EGFR TKI in 1L EGFR mutated NSCLC is ongoing to verify these observations (NCT01774721).
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MINI05.09 - Discussant for MINI05.06, MINI05.07, MINI05.08 (ID 3323)
16:45 - 18:15 | Author(s): R. Martins
- Abstract
- Presentation
Abstract not provided
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- Abstract
- Presentation
Background:
Radiotherapy is the principal treatment modality for patients with brain metastases (BM), however, tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR) shows therapeutic efficacy for brain metastases in patients with EGFR-mutant lung adenocarcinoma. This study was conducted to compare the outcome of TKI alone with TKI plus concomitant radiotherapy in treatment of BM from EGFR-mutated lung adenocarcinoma patients.
Methods:
The inclusion criteria were as following: patients newly diagnosed with EGFR-mutant lung adenocarcinoma, presented with BM, TKI as first-line therapy, and ECOG PS 0-2.
Results:
From January 1, 2009 to September 1, 2014 at Zhengzhou University Affiliated Cancer Hospital, 516 lung adenocarcinoma patients with EGFR gene mutations were reviewed, and 132 cases (25.6%) with newly diagnosed BM were enrolled for the analysis. Among the 132 patients, more than half of them (n = 72; 54.5%) harbored a deletion in exon 19, 97 patients (73.5%) showed multiple intracranial lesions, and 50.8% (n = 67) had asymptomatic BM. 79 patients (59.8%) were treated with TKI alone, 53 with TKI plus concomitant radiotherapy (45 with whole brain radiotherapy, and 8 with stereotactic radiosurgery). The objective response rate of BM was significantly higher in TKI plus radiotherapy group (67.9%) compared with TKI alone group (27.8%, P<0.001). The median time to intracranial progression was 22.3 months. The median intracranial progression-free survival in patients who received TKI plus radiotherapy was 24.7 months, much longer than those treated with TKI alone which was 19.0 months, P = 0.005. Multivariate analysis showed brain radiotherapy (P = 0.012) and intracranial lesion number (P = 0.070) as important prognostic factors for intracranial progression-free survival. In addition, the data of overall survival will be presented at the conference.
Conclusion:
For EGFR-mutated lung adenocarcinoma patients with BM, TKI plus concomitant radiotherapy achieved higher response rate of BM and significant improvement in intracranial progression-free survival compared with TKI alone. Figure 1
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MINI05.11 - Exon 19 Deletion Prolongs Survival in Brain Metastases from Non-Small Cell Lung Cancer (ID 417)
16:45 - 18:15 | Author(s): H. Li
- Abstract
- Presentation
Background:
Approximately 20-40% of non–small–cell lung cancer (NSCLC) patients develop brain metastasis (BM) and the survival is very poor with a median overall survival of 4-6 months following whole brain radiotherapy treatment. Recent studies have shown that oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were effective for the treatment of BM from NSCLC with EGFR mutation. However, the relationship between EGFR mutations and prognosis of NSCLC patients with BM remains to be determined. In this study, we investigated the impact of EGFR mutation status on the survival of BM patients from NSCLC
Methods:
730 NSCLC patients were retrospectively reviewed. 136 patients had developed BM during their course of disease. 33 of these 136 BM patients (24.3%) were confirmed to have exon 19 deletions, while 33 had exon 21 point mutation (L858R) (24.3%). Overall survival was evaluated by Kaplan-Meier method. Log-rank test and Cox proportional hazards model were used to analyze the impact of pretreatment and treatment variables on survival.
Results:
The median survival of NSCLC with BM was 8 months. Log-rank test analysis showed that ECOG PS at BM (p=0.000), control of primary tumor (p=0.005), pathology (p=0.01), EGFR mutations (p=0.045) and 19 exon deletion (p=0.007) were associated with a longer survival. In Cox proportional hazards model, EGFR exon 19 deletion (HR=0.558, 95%CI=0.325-0.957, p=0.034), control of primary tumor (HR=2.033, 95%CI=1.098-3.766, p=0.024), and ECOG PS at BM (HR=2.033,95%CI=1.145-1.287, p=0.006) were found to be independent prognostic factors. Moreover, there were significantly differences in the survival between different groups according to RTOG recursive partitioning analysis (RPA) classification system in this cohort of patients (p=0.000)
Conclusion:
Exon 19 deletion is an independent prognostic factor in BM from NSCLC. Our findings suggest that the status of exon 19 deletion may be integrated into the prognostic scoring classification system for NSCLC.
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- Abstract
- Presentation
Background:
Erlotinib has a synergistic effect with pemetrexed when treating non-squamous non-small cell lung cancer. The aim of our study was to confirm the efficacy and safety of erlotinib (E) in combination with pemetrexed/cisplatin (E-P) in Chinese lung adenocarcinoma with brain metastases.
Methods:
This study is a prospecive, non-randomized cocurrent controlled study. Lung adenocarcinoma patients with brain metastases, who were erlotinib or pemetrexed treatment-naive and had adequate organ functions, were assigned in parallel to receive either erlotinib 150 mg/day or erlotinib on days 4-21 plus pemetrexed 500 mg/m[2] on day 1 and cisplatin 20 mg/m[2] on day 1-3 every 21 days up to 6 cycles and subsequent oral erlotinib, until progressive disease or unacceptable toxicity. The primary endpoint was intracranial overall response rate (ORRi). Previous data showed that about 56% of the patients treated with E and 78% of the patients treated with E-P, achieved an ORRi. We estimated the minimum sample size of 65 with 70% power (two-sided alpha 0.05).
Results:
69 lung adenocarcinoma patients with brain metastases had received E (n=35) or E-P (n=34) from Jan 2012 through Nov 2014. Demographics and patient characteristics were well balanced between two groups, including EGFR status, gender, age, smoking status, ECOG performance status, brain metastases and number of prior treatments. ORRi, in the E-P arm was superior to that in the E arm (79% vs. 48%, P=0.008) (Table S). Especially in the patients with EGFR wild type or treated as first-line treatment could achieve much better ORRi. Patients treated with E-P arm, compared with E arm as first-line treatment, were associated with better intracranial PFS (PFSi) (median PFSi, 9 months vs. 2 months, P=0.02) and systemic PFS (median PFS, 8 months vs. 2 months, P=0.006).The most frequent adverse events related with erlotinib were higher in the combination arm. No new safety signals were detected. The side effects were tolerable and no-drug related deaths. Table S The ORRi between the E-P and E armgroup (n) ORRi (n,%） Total patients E (35) 17,48.6% E-P (34) 27, 79.4% P value 0.008 EGFR mutation E (18) 10,55.6% E-P (14) 12,85.7% P value 0.124 EGFR negative E (7) 1, 14.3% E-P (11) 7, 63.6% P value 0.066 EGFR unknown E (10) 6,60.0% E-P (9) 8,88.9% P value 0.303 First-line treatment E (16) 7,43.7% E-P (18) 14 ,77.7% P value 0.08
Conclusion:
The combination of erlotinib and pemetrexed/cisplatin is effective and improved PFS as first-line treatment in Chinese lung adenocarcinoma with brain metastases. Toxicities are tolerable and the erlotinib-related side-effects were higher.
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MINI05.13 - Treatment of EGFR/ALK-Driven Non-Small Cell Lung Cancer (NSCLC) Brain Metastases: Impact of First-Line Whole Brain Radiotherapy on Outcome (ID 1251)
16:45 - 18:15 | Author(s): M.K. Doherty, G. Korpanty, P. Tomasini, M. Alizadeh, K. Jao, C. Labbe, C. Mascaux, P. Martin, S. Kamel-Reid, M. Pintilie, G. Liu, P. Bradbury, R. Feld, N. Leighl, C. Chung, F. Shepherd
- Abstract
- Presentation
Background:
Brain metastases (mets) in EGFR/ALK-driven NSCLC are common, and frequently pose treatment dilemmas. Effective systemic therapy with tyrosine kinase inhibitors (TKIs) controls extracranial disease in up to 70% of patients, but often radiotherapy is required for intracranial control. As whole brain radiation (WBRT) may be associated with neurocognitive toxicity, we aimed to evaluate the impact of molecularly targeted therapy and stereotactic radiotherapy (SRS) for EGFR/ALK-driven NSCLC on intracranial disease control with and without WBRT.
Methods:
This retrospective analysis included patients treated with EGFR/ALK-positive NSCLC at Princess Margaret Cancer Centre from 1998-2015, with brain mets at lung cancer diagnosis or during treatment/follow-up. Demographic data were collected from electronic patient records. Time to intracranial progression (TTIP) and overall survival (OS) were calculated from date of diagnosis of brain mets, using the cumulative incidence function and Kaplan-Meier methods respectively; differences between groups were tested with Gray’s or log-rank test.
Results:
From 1998-2015, 162 patients with brain mets from EGFR/ALK-driven NSCLC were identified: 138 in the EGFR cohort, 23 in the ALK cohort and one included in both cohorts for analysis, whose tumour carries both an EGFR mutation and ALK rearrangement. Table 1 contains clinical characteristics and treatment details. In the EGFR cohort, initial brain mets treatment consisted of systemic therapy alone in 19 patients (17 TKI, 2 chemotherapy), SRS +/- surgery in 27 patients and WBRT +/- SRS/surgery in 88 patients. 1-year intracranial progression rates were 26%, 32% and 12%, respectively, and median TTIP was 18, 16 and 40 months [p=0.12]. Median OS was 26, 27 and 34 months respectively [p=0.49]. In the ALK cohort, initial brain mets treatment consisted of systemic therapy alone in 4 patients (1 TKI, 3 chemotherapy), SRS/surgery alone for 4 patients and WBRT +/- SRS/surgery for 15 patients. 1-year intracranial progression rates were 50%, 50% and 13%, respectively, and median TTIP was 18, 14 and 69 months [p=0.028]. Median OS was 35 months, not reached and 51 months, respectively [p=0.75]. Multivariable analysis for the whole group showed that age [p=0.021], number of brain mets [p=0.012] and extracranial control [p=0.008] were significantly associated with OS, but not WBRT [p=0.61].
Conclusion:
In this cohort of patients with brain mets from EGFR/ALK-driven NSCLC, patients treated with WBRT trended to longer TTIP. Although not statistically significant, our data also show a trend towards longer survival in patients who received WBRT. These observations require further validation in this patient population.EGFR (N=139) ALK (N=24) Median Age (Range) 59(29-86) 53(31-77) Female Sex 93(67%) 15(62%) Ethnicity Asian Caucasian Other 58(42%) 63(45%) 18(13%) 7(29%) 13(54%) 4(17%) Smoking Never Smoker Former/Current Smoker Unknown 108(77%) 30(22%) 1(1%) 19(79%) 5(21%) 0 ECOG PS (Diagnosis) 0 1 2-4 66(48%) 67(48%) 6(4%) 7(29%) 14(58%) 3(13%) Brain Mets at Stage IV diagnosis 93(67%) 13(52%) Number of Brain Mets 1 2-4 5+ N/A 32(23%) 39(28%) 62(45%) 6(4%) 9(38%) 6(24%) 9(38%) 0 Symptomatic Brain Mets No Yes 78(56%) 61(44%) 16(67%) 8(33%) Initial Brain Mets treatment WBRT WBRT+SRS/Surgery SRS+/-Surgery Systemic Therapy None 71(51%) 17(12%) 27(19%) 19(14%) 5(4%) 13(54%) 3(12%) 4(17%) 4(17%) 0
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MINI05.14 - Discussant for MINI05.10, MINI05.11, MINI05.12, MINI05.13 (ID 3324)
16:45 - 18:15 | Author(s): B.J. Solomon
- Abstract
- Presentation
Abstract not provided
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Author of
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MINI 26 - Circulating Tumor Markers (ID 148)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:M. Macmanus, C. Aggarwal
- Coordinates: 9/09/2015, 16:45 - 18:15, 205+207
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MINI26.15 - Discussant for MINI26.11, MINI26.12, MINI26.13, MINI26.14 (ID 3378)
16:45 - 18:15 | Author(s): R. Perez-Soler
- Abstract
- Presentation
Abstract not provided
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-102 - Phase I Study of Inhaled 5-Azacytidine in Patients with Advanced NSCLC (ID 546)
09:30 - 17:00 | Author(s): R. Perez-Soler
- Abstract
Background:
Epigenetic changes due to promoter hypermethylation have been shown to cause loss of tumor suppressor gene (TSG) function in NSCLC. Significant toxicity and lack of tumor selectivity have been the main limitations of systemic demethylating agents. We previously showed that aerosolized 5-Azacytidine (Aza) was superior to systemic administration in prolonging the survival of mice with carcinogen-induced lung cancer. These results suggest that inhaled Aza could inhibit lung cancer initiation and progression in subjects with chronic airborne carcinogen exposure. Thus, we designed the first phase I study of aerosolized Aza to determine the minimum effective dose of inhaled Aza required to induce relevant TSG re-expression in the bronchial epithelium of patients with advanced NSCLC.
Methods:
This is a phase I study following a 6+6 dose escalation and de-escalation design. Patients with advanced NSCLC, who have received at least one prior standard chemotherapy or targeted therapy, with ECOG PS 0-1, and adequate baseline bone marrow reserve, pulmonary reserve, and organ function are eligible. This study has received IRB and FDA approval as of 01/2015. Patients will be treated with inhaled Aza daily (20-minute inhalation) x 5 days per week once every 2 weeks. Based on our toxicity studies in mice, the recommended starting dose is 15 mg/m[2] . Dose escalation will proceed if <33% subjects in a given cohort experience pre-defined dose limiting toxicity (DLT) defined as grade 2 or higher pulmonary toxicity, grade 4 anemia, neutropenia, thrombocytopenia or any grade 3 or higher non-hematologic toxicity. The primary objective of the study is to determine the minimum effective dose of inhaled Aza required to induce re-expression of 5 relevant candidate TSGs (p16, H-Cad, OPCML, SFRP-1, and RASSF1A) that are silenced in the bronchial tissue of 20-50% heavy smokers with lung cancer. This will be determined in the bronchial epithelium of patients with advanced NSCLC in pre and post treatment biopsies. Secondary objectives include determining changes in global methylation patterns in the bronchial epithelium, and changes in methylation patterns in the exhaled breath. Clinical trial information: NCT02009436. Supported by NIH CA154755
Results:
not applicable
Conclusion:
not applicable
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PLEN 04 - Presidential Symposium Including Top 4 Abstracts (ID 86)
- Event: WCLC 2015
- Type: Plenary
- Track: Plenary
- Presentations: 1
- Moderators:T. Mok, F.R. Hirsch
- Coordinates: 9/09/2015, 10:45 - 12:15, Plenary Hall (Bellco Theatre)
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PLEN04.03 - Randomized Phase III Trial of Adjuvant Chemotherapy with or without Bevacizumab in Resected Non-Small Cell Lung Cancer (NSCLC): Results of E1505 (ID 1608)
10:45 - 12:15 | Author(s): R. Perez-Soler
- Abstract
- Presentation
Background:
Adjuvant chemotherapy for resected early stage NSCLC provides modest survival benefit. Bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor, improves outcomes when added to platinum-based chemotherapy in advanced stage non-squamous NSCLC. We conducted a phase 3 study to evaluate the addition of bevacizumab to adjuvant chemotherapy in early stage resected NSCLC. The primary endpoint was overall survival and secondary endpoints included disease-free survival and toxicity assessment.
Methods:
Patients with resected stage IB (>4 centimeters) to IIIA (AJCC 6th edition) NSCLC were enrolled within 6-12 weeks of surgery and stratified by chemotherapy regimen, stage, histology and sex. All patients were to receive adjuvant chemotherapy consisting of a planned 4 cycles of every 3 week cisplatin at 75 mg/m[2] with either vinorelbine, docetaxel, gemcitabine or pemetrexed. Patients were randomized 1:1 to arm A (chemotherapy alone) or arm B, adding bevacizumab at 15 mg/kg every 3 weeks starting with cycle 1 of chemotherapy and continuing for 1 year. Post-operative radiation therapy was not allowed. The study had 85% power to detect a 21% reduction in the overall survival (OS) hazard rate with a one-sided 0.025-level test.
Results:
From July 2007 to September 2013, 1501 patients were enrolled. Patients were 49.8% male, predominantly white (87.9%) with a median age of 61 years. Patients enrolled had tumors that were 26.2% stage IB, 43.8% stage II and 30.0% stage IIIA and 28.2% of patients had squamous cell histology. Chemotherapy options were utilized with the following distribution: vinorelbine 25.0%, docetaxel 22.9%, gemcitabine 18.9% and pemetrexed 33.2%. At a planned interim analysis, with 412 of 676 overall survival events needed for full information (60.9%), though the pre-planned futility boundary was not crossed, the Data Safety Monitoring Committee recommended releasing the trial results based on the conditional power of the logrank test. At the time of interim analysis, with a median follow-up time of 41 months, the OS hazard ratio comparing the bevacizumab containing arm (Arm B) to chemotherapy alone (Arm A) was 0.99 (95% CI: 0.81-1.21, p=0.93). The DFS hazard ratio was 0.98 (95% CI: 0.84-1.14, p=0.75). Completion of treatment per protocol was 80% on Arm A and 36% on Arm B. Statistically significantly increased grade 3-5 toxicities of note (all attributions) included: overall worst grade (67% versus 84%); hypertension (8% versus 30%), and neutropenia (33% versus 38%) on Arms A and B, respectively. There was no significant difference in grade 5 adverse events per arm with 16 (2%) on arm A and 19 (3%) on arm B.
Conclusion:
The addition of bevacizumab to adjuvant chemotherapy failed to improve survival for patients with surgically resected early stage NSCLC.
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