2015年欧洲肺癌大会（ELCC）摘要

1. Brigatinib (AP26113) Shows Intracranial Anti-tumour Activity in ALK-positive NSCLC patients with Brain Metastasis Following Crizotinib
——对ALK阳性、经Crizotinib治疗后的脑转移NSCLC患者，AP26113显示颅内抗肿瘤活性

More than 80% of patients with non-small-cell lung cancer (NSCLC) and brain metastases achieved intracranial disease control after treatment with brigatinib, formerly AP26113, an investigational ALK tyrosine kinase inhibitor that can be taken orally.

Central nervous system (CNS) progression has been observed in a significant proportion of patients treated with crizotinib for ALK-positive NSCLC, according to first author Dr David Kerstein, Clinical Research, ARIAD Pharmaceuticals, Inc., Cambridge, USA. Dr Kerstein presented findings from this post hoc efficacy analysis during a Medical and Radiation Oncology poster discussion session at the European Lung Cancer Conference, held April 15 to 18, 2015 in Geneva, Switzerland.

The post hoc analysis was done on data from 45 of the 49 patients identified with baseline brain metastases that had evaluable data at cut-off. The patients were among participants in a larger phase 1/2 single-arm, multicentre study of brigatinib in patients with advanced malignancies. All patients received brigatinib at total daily doses of 30 to 300 mg orally once daily.

Preclinical activity for brigatinib had been observed against mutated ALK and also in crizotinib-resistant tumours having a range of other mutations in patients with baseline intracranial CNS metastases, which led to Breakthrough Therapy designation by the US Food and Drug Administration (FDA) in 2014.

Contrast-enhanced magnetic resonance imaging of the brain was done at baseline and at follow-up that was centrally reviewed by blinded independent neuroradiologists. Lesions having a longest diameter of 10 mm or greater were defined as measurable lesions.

The 49 patients identified with baseline brain metastasis and having evaluable data were on study a median of 56.1 weeks. Measurable brain metastases were reported for 16 patients and non-measurable brain metastases for 33 patients. Following treatment, 45 patients overall with brain involvement and a follow-up scan achieved median intracranial progression–free survival (PFS) of 22.3 months and the median duration of intracranial response in 16 patients with a response and a follow-up scan was 18.9 months.

Intracranial response was reported for 8 (53%) patients with measurable brain metastases and for 9 (30%) patients identified with non-measurable lesions. Intracranial disease control was achieved by 13 (87%) patients with measurable and by 26 (87%) patients with non-measurable brain metastases.

Treatment-emergent adverse events were mild to moderate in severity and included nausea, diarrhoea, and fatigue that were reported by 29 (59%), 28 (57%) and 24 (49%) patients, respectively.

Prof. Giorgio Scagliotti from the University of Torino in Italy, who discussed the study results, said that a clinical development of ALK inhibitors is amazing in very short time period. Second generation of ALK inhibitors is characterised by high response rate and penetration into central nervous system with highly efficacy against untreated and treated brain metastases.

Conclusions

The investigators concluded that brigatinib demonstrated significant intracranial antitumor activity and durable responses in patients with ALK-positive NSCLC whose disease progressed following crizotinib therapy and demonstrated CNS metastases at baseline.

Based on results from this post hoc analysis, a prospective study of brigatinib in ALK-positive NSCLC patients with brain metastases participating in the phase II ALTA trial is underway.

Reference

LBA4. Evaluation of anaplastic lymphoma kinase (ALK) inhibitor brigatinib [AP26113] in patients (pts) with ALK+ non-small cell lung cancer (NSCLC) and brain metastases.

2. VEGF SNPs Identified as Prognostic Markers for Bevacizumab Response in Patients with Advanced Non-Squamous NSCLC

Patients with advanced non-squamous non-small-cell lung cancer (NS-NSCLC) achieved median overall survival (OS) longer than one year in ANGIOMET, a prospective clinical trial of bevacizumab plus carboplatin and paclitaxel, leading the investigators to look for and identify biomarkers for this response.

Prof. Bartomeo Massuti Sureda, Department of Medical Oncology, Hospital General Universitario de Alicante, Alicante, Spain, presented the final efficacy results and identification of predictive biomarkers from the ANGIOMET trial on behalf of the Spanish Lung Cancer Group at the European Lung Cancer Conference, held 15 – 18 April 2015 in Geneva, Switzerland.

The ANGIOMET (analysis of the correlations between angiogenic markers and outcome in patients with advanced NS-NSCLC treated with carboplatin, paclitaxel, and bevacizumab) trial treated patients with advanced stage IIIB/IV NS-NSCLC (ECOG performance status 0-2) with first-line carboplatin/paclitaxel plus bevacizumab for six cycles, which were followed by maintenance with bevacizumab.

The trial enrolled 202 patients with median age of 61 years (range: 37 to 80 years). The majority (67.2%) of patients were male and 97.8% had stage IV disease, which was mostly (88.2%) adenocarcinoma. All patients (100%) were Caucasian and 15.8% of patients were never-smokers. The per protocol population comprised 199 patients who received a median five cycles of carboplatin/paclitaxel plus bevacizumab.

Clinical benefit is demonstrated with carboplatin/paclitaxel plus bevacizumab treatment in patients with advanced non-squamous NSCLC

The trial’s primary endpoint, progression-free survival (PFS) was met; patients achieved median PFS of 6.91 months (range: 6.16-7.65).

Overall survival (OS) and response rate (RR) were secondary endpoints; patients experienced OS of median 14.57 months (range: 11.83 to 17.31 months). In the intent-to-treat population of 171 patients, 1% of patients achieved complete response, 49% had partial response, stable disease was seen in 36% of patients and progressive disease occurred in 10.6% of patients. Response in 4% of patients was not evaluated.

Ancillary study identifies specific single nucleotide polymorphisms in angiogenic factors as predictive markers for outcome

European Lung Cancer Conference 2015: Abstract 37PD
Ten SNPs analysed in the ANGIOMET study and their correlation with progression-free survival
© Bartomeu Massuti Sureda
Prof. Massuti Sureda discussed results from the ancillary study that was designed to investigate the relationship between the response to this treatment, patient outcomes, and angiogenic mediators.

The ancillary study focused on molecules in the VEGF pathway where several ligands and receptors have been characterised as important in tumour angiogenesis and therapeutic efficacy. The investigators hypothesized that single nucleotide polymorphisms (SNPs) could modify levels of angiogenic factors in the tumour or blood and may associate with prognosis and outcomes with bevacizumab.

Blood samples were collected from patients prior to and after treatment, and DNA was obtained from the leukocyte fraction. Polymerase chain reaction (PCR) assay was used to genotype SNPs of angiogenic genes and plasma levels of VEGFA and VEGFR2 were determined by ELISA.
Upon analysis, shorter PFS (p = 0.01) and OS (p = 0.01) were found to associate with VEGFR1 SNP rs9582036. VEGFA SNP rs3025039 associated with poorer OS when compared to other genotypes (p = 0.009).

However, lower levels of circulating VEGF were prognostic of better outcome; a significant association with longer PFS (p = 0.04) and a trend toward improved OS (p = 0.10) was identified.

Prof. Giorgio Scagliotti from the University of Torino in Italy, who discussed the results, said that the study hypothesis was if SNPs could modify levels of angiogenic factors in tumour or serum/plasma and if they have a prognostic/predictive  impact. However, the search for reliable biomarkers predicting the efficacy of anti-angionetic therapies remains an open issue.  Potential surrogate markers for the evaluation of anti-VEGF agents could be invasive (tissue biopsy, interstitial fluid pressure measurement, measurement of tissue oxygenation, skin wound healing), minimally invasive (circulating endothelial cells, circulating progenitor cells, protein levels in plasma, VEGF polymorphisms), non-invasive such as imaging (CT imaging, PET imaging, MRI) and clinical (hypertension, gender, urine protein, e.g. MMP, VEGF).

Conclusion

The investigators found no significant association between response rates and either the SNPs analysed or levels of VEGF and VEGFR2 in patient blood samples. However, patients having lower VEGF levels in their baseline blood samples experienced improved survival outcomes.

Furthermore, it was determined that the presence of certain VEGFR1 and VEGFA SNPs in the blood of patients with advanced NS-NSCLC associated with decreased efficacy of the bevacizumab, carboplatin and paclitaxel regimen that was demonstrated by shorter PFS and OS.

Reference

37PD. SNPs in angiogenic factors as predictive markers for outcome in patients (p) with advanced non-squamous NSCLC (NS-NSCLC) treated with carboplatin, paclitaxel (CP) and bevacizumab (Bev). Final results of ANGIOMET Spanish Lung Cancer Group Trial

3. EGFR Mutation Detection Possible from Ultrasound-Guided Fine Needle Aspirates Taken from Patients with Lung Cancer

Samples taken by the currently approved method of ultrasound (US) guided fine needle aspiration (FNA) for detection of supraclavicular and cervical lymphadenopathy in patients with lung cancer could also be used for epidermal growth factor receptor (EGFR) mutation analysis, thereby decreasing or eliminating the need to take additional invasive samples.

These findings were presented by Prof. Amir Awwad, Department of Radiology, Nottingham University Hospitals NHS Trust, Queen's Medical Centre, Nottingham, UK on behalf of colleagues in a poster on during a Poster session at the European Lung Cancer Conference, held April 15-18, 2015 in Geneva, Switzerland.

EGFR mutation status is an important tool in guiding the clinical choice of targeted therapies for lung cancer.

The authors pointed out that supraclavicular and cervical lymphadenopathy occurs in 15% to 30% of patients with lung cancer and, while US-guided FNA cytology serves as an effective diagnostic tool in small size lymph nodes and impalpable Positron Emission Tomography (PET) detected nodes, there was a paucity of data exist on whether this techniques can also provide information on EGFR mutation. They evaluated US-guided analysis of supraclavicular and cervical lymphadenopathy samples for the specificity and sensitivity in detection of EGFR mutations.

The team performed a retrospective data analysis from the electronic records of 306 patients with suspected lung cancer that had been referred for US-guided FNA of supraclavicular and cervical lymphadenopathy over a four-year period. Of these, 228 patients underwent the procedure and a cytological diagnosis was established in 171 (75%) patients for treatment decisions without further investigations.

Further investigative tests that included core lymph node biopsy, bronchial washings and lung biopsy were done in 57 patients; the diagnosis made by US-guided FNA was re-confirmed in 45 (75%) patients.

Positive cytology could be performed in lymph nodes ranging from 3 to 45 mm and the average lymph node size was 12.9 mm.

Ultrasound-guided supraclavicular lymph node fine-needle aspirates can provide reliable EGFR mutation testing with high sensitivity and specificity

EGFR testing was done in 34 of the 57 patients with adenocarcinoma. Four samples were positive for EGFR mutation, 25 were negative and 5 samples were insufficient for EGFR mutation analysis.

The investigators compared US guided FNA by statistical methods to a composite of all further tests used to identify EGFR mutations and found that US guided FNA had sensitivity of 76.9% (95% CI 63.2%, 87.5%) and specificity of 100% (95% CI 47.9%, 100%).

The positive predictive values of US guided FNA was 100% in comparison to all further tests, core lymph node biopsy, bronchial washings and lung biopsy, The negative predictive value of US guided FNA was 29.4%, 20%, 42.9% and 25% compared to all, further tests, core lymph node biopsy, bronchial washings and lung biopsy, respectively. The negative likelihood ration was 0.23, 0.18, 0.3 and 0.4, for US guided FNA compared to all, further tests, core lymph node biopsy, bronchial washings and lung biopsy. The positive likelihood ratio was not available for all parameters.

Patients reported no complication related to any of the procedures performed.

Conclusion

Based on results contained in this poster Prof. Awward stated that it may not be necessary for determination of EGFR mutation status to obtain additional samples by alternative methods such as bronchial washings and lung or core lymph node biopsy when US-guided FNA have already been taken from patients with lung cancer.

The investigators concluded that, in most patients, US guided FNA provided reliable EGFR mutation status that was highly sensitive and specific. Furthermore, US guided FNA gave better positive predictive value information on EGFR mutation in comparison to the other techniques used in this study.

Reference

5P. Reliable EGFR mutation testing in ultrasound guided supraclavicular lymph node fine needle aspirates: A cohort study with diagnostic performance analysis

4. Promising Results for Surgical Salvage of Local Recurrences after Stereotactic Ablative Radiotherapy in Patients With Early-Stage NSCLC

5. Neoadjuvant Erlotinib in Endobronchial Ultrasound Confirmed Stage IIIA-N2 NSCLC

Erlotinib showed promise as neoadjuvant therapy in patients with epidermal growth factor receptor (EGFR) mutant stage IIIA-N2 non-small-cell lung cancer (NSCLC) who demonstrated good disease control with tolerable toxicity following treatment.

Dr Baohui Han, Pulmonary Department, Shanghai Chest Hospital, Shanghai, China presented findings from a single arm, phase II clinical trial during the New Treatment Avenues Proffered Papers session at the European Lung Cancer Conference, 15 to 18 April 2015 in Geneva, Switzerland. The trial aimed to evaluate efficacy and safety of erlotinib as neoadjuvant treatment in patients with stage IIIA-N2 NSCLC and activating EGFR mutation.

                               
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Erlotinib as neoadjuvant treatment in endobronchial ultrasound confirmed stage IIIA-N2 NSCLC patients with EGFR mutation (exon 19 or 21), ESTERN: A prospective, single arm, phase II clinical trial.
© Baohui Han

The trial’s primary endpoint was radical resection rate. Secondary endpoints included pathological complete response rate (pCR), objective response rate (ORR), disease free survival (DFS), overall survival (OS), safety profile, and explorative biomarkers.

This study screened 155 patients and subsequently enrolled 44 patients with stage IIIA N2 NSCLC and 25 patients with IIIA N2 NSCLC plus activating EGFR (exon 19 or 21) mutations. All patients had ECOG performance status 1 and had been previously untreated for stage IIIA-N2 NSCLC, that was confirmed by endobronchial ultrasound.

During the 56-day neoadjuvant phase, all patients received erlotinib 150 mg orally per day. Only patients that showed benefit from erlotinib and were evaluated as resectable following the neoajuvant treatment phase received surgery.

Following erlotinib treatment, the response rate was 32% and the disease control rate was 76%; 16 patients were evaluated as resectable and underwent surgery. R0 resection was performed in 15 (93.8%) patients, which yielded a resection rate of 60%. The pCR was 6.3% and the pathological resection rate (pRR) was 93.7%.

Following surgery, patients received long-term follow-up including a quarterly chest CT scan for up to 2 years. The post-surgical median DFS (from operation) was 10.4 months. OS data are not yet mature.
EGFR mutation status remained unchanged before and after the surgery in most patients with the exception of 3 patients with an exon 19 deletion that changed to EGFR wild type after resection.

There were a few adverse events following erlotinib treatment and most were mild; 7 (28%) patients had grade I rash and one (4%) patient had grade I diarrhoea. One patient with hepatitis comorbidity had grade IV abnormal liver function. One patient experienced a serious adverse event, cerebral infarction, with neoadjuvant erlotininb.

Dr Wilfried Eberhardt of the West German Cancer Centre in Essen, who discussed the results, said that the study authors presumed that induction therapy in EGFR mutation positive stage IIIA(N2) NSCLC patients is comparably effective for downstaging and downsizing as induction chemotherapy. Never smoker and women seem to have the most benefit from such an approach. However, PFS and DFS results are not convincing yet.

The majority of patients in this study did not receive the standard number of adjuvant chemotherapy cycles (n = 4). Therefore, a historical comparison to patient groups with surgery plus adjuvant chemotherapy is significantly hampered.

Dr Eberhardt expressed criticism that a restriction to common mutations and never smoker and women may be more suitable than to investigate such an approach in a curative setting unselectively. He questioned the best time and schedule of adjuvant/neoadjuvant chemotherapy in such setting that is currently unknown and said that chemotherapy is actually proven to be curative in this setting.

Conclusions

The authors concluded that erlotinib as neoadjuvant therapy is a promising treatment for patients with EGFR mutant IIIA-N2 NSCLC that resulted in most patients being evaluated as resectable and elegible for surgical resection of tumours. The findings need to be further confirmed in a prospective phase III trial. Patients showed tolerable toxicity with neoadjuvant erlotinib with a serious adverse event occurring in just one patient.

Reference

81O. Erlotinib as neoadjuvant treatment in endobronchial ultrasound confirmed stage IIIA-N2 non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation (Exon 19 or 21) (NCT01217619, ESTERN): A prospective, single arm, phase II clinical trial.

6. ‘Real-World’ EGFR Mutation Frequency Results From a Large Population of Chemotherapy Naive Patients With Advanced NSCLC

Findings from IGNITE, a large, multinational (China, Russia, Indonesia, Taiwan, Singapore, Thailand, Australia, South Korea and Malaysia), diagnostic, non-comparative, interventional study, were presented by lead investigator Dr Baohui Han, Pulmonary Department, Shanghai Chest Hospital, Shanghai, China during the New Treatment Avenues Proffered Papers session at the European Lung Cancer Conference, 15-18 April 2015 in Geneva, Switzerland.

Enrollment was carried out in 90 centres and included 3382 patients with advanced non-small-cell lung cancer (NSCLC) of both adenocarcinoma (ADC) and non-ADC histology. Patients were chemotherapy naive, and had local and/or metastatic NSCLC that was either newly diagnosed or represented recurrent disease after resection. All patients were evaluated as ineligible for curative treatment.

The primary endpoint of IGNITE was the determination of EGFR mutation frequency by locally tested samples. Secondary endpoints included the concordance of EGFR mutation status between matched tissue/cytology and plasma, specifically circulating-free tumour-derived DNA, correlation between mutation status and demographic/disease status, treatment decisions, and EGFR testing practices.

EGFR mutation frequency varies by country, sample type, and histology

European Lung Cancer Conference 2015: Abstract 96O
Determining the prevalence of EGFR mutations in Asian and Russian patients with advanced non-small-cell lung cancer (aNSCLC) of adenocarcinoma (ADC) and non-ADC histology: IGNITE study.
© Baohui Han
Tissue and/or cytology were evaluable in 2291 Asian and 924 Russia patients and plasma was evaluable in 1753 Asian and 941 Russian patients, within a median test turnaround of 6 and 9 days, respectively.

Among the Asian patient population the EGFR mutation frequency by tissue/cytology was 49% in ADC, 14% in non-ADC and 10% in squamous cell carcinoma, whereas in the Russian population the EGFR mutation frequency was 18% in ADC, 4% in non-ADC, and 4% in squamous cell carcinoma. The EGFR mutation frequency was lower in plasma with an overall frequency of 22% in ADC and 7% in non-ADC samples.

The most frequently observed mutation overall was Exon 19 deletion only (49% Asia Pacific, 59% Russia), followed by L858R only (42% Asia Pacific, 25% Russia), Exon 20 insertions only (2% Asia Pacific, 0% Russia), L861Q only, and G719X (both ≤1% overall).

Mutation status concordance could be determined in 2581 matched samples.  EGFR mutation status concordance data for tumour vs. plasma showed that sensitivity (50% vs. 30%) and positive predictive value (93% vs. 39%) were higher in Asia Pacific vs. Russia, respectively.

EGFR mutation status was the largest driver of treatment choice in both patients with mutation-positive (50%/47% in Asia Pacific/Russia) and mutation-negative (38%/43% in Asia Pacific/Russia) NSCLC. Following EGFR mutation testing, the most common first-line treatment overall for patients with EGFR mutation-positive NSCLC was gefitinib (36%), and for patients with EGFR mutation-negative NSCLC was cisplatin (41%); however, this pattern differed between Asia Pacific and Russia. Use of tyrosine kinase inhibitors in patients with EGFR mutation-positive NSCLC varied widely within AsiaPacific, ranging from 92% in Taiwan to 0% in Thailand.

EGFR mutation frequency significantly associates with specific patient demographics and diagnoses

ADC and never-smoker status significantly associated with the mutation frequency in the overall population (both, tissue/cytology and plasma status, p < 0.0001). In the Asian versus the Russian cohort (both, p < 0.0001), greater number of metastatic organs (tissue/cytology p = 0.0909 and plasma p < 0.0001), female gender (tissue/cytology only p = 0.0075) and age 65 years or greater (plasma only; p = 0.0009) significantly associated with EGFR mutation frequency.

Immunohistochemistry analyses showed that 10% of TTF-1-negative patient samples were EGFR mutation-positive. Similarly, 44% of TTF-1-positive patient samples were EGFR mutation-positive.

Dr Wilfried Eberhardt of the West German Cancer Centre in Essen, who discussed the results, said that there is still little known about the worldwide epidemiology of EGFR mutations in lung cancer patients. Until now, several national groups have investigated the prevalence of EGFR mutations in large patient subsets. In general, EGFR mutation rate in Asian patients was considerably higher than that in non-Asians.

This study looked at the prevalence of EGFR mutations in Asia and Russia. The results of nearly 50% of EGFR mutations in patients with lung adenocarcinoma in Asia and about 20% EGFR mutated adenocarcinoma in Russia points to specific selection factors. So, these data are probably not representative for the whole population in Asia and Russia.

Data from Russia include more stage IIIA and IIIB patients that represent different patient subsets. Moving EGFR tyrosine kinase inhibitor (TKI) therapy into patient groups with early and locally advanced NSCLC may be more difficult than initially thought.

Dr Eberhardt said that only a bit more than one third of the patients received EGFR TKI in the first-line setting. These data seem realistic for the everyday practice setting.

With broader testing frequencies for EGFR mutations, epidemiological and prevalence data for EGFR mutations should become more precise.

Conclusions

Dr Han concluded that these data from chemotherapy-naive patients with advanced NSCLC in the ‘real world’ suggest that EGFR mutation frequency is higher in patients with ADC versus non-ADC histology. However, he cautioned that mutations in the non-ADC population were seen at a frequency that supports mutation testing for all patients.

Reference

96O. Determining the prevalence of EGFR mutations in Asian and Russian patients (pts) with advanced non-small-cell lung cancer (aNSCLC) of adenocarcinoma (ADC) and non-ADC histology: IGNITE study

7. Evidence Grows that Melanoma Drugs Benefit some Lung Cancer Patients

Geneva, Switzerland -- A subset of lung cancer patients can derive important clinical benefits from drugs that are more commonly used to treat melanoma, the authors of a new academic clinical trial in Europe have reported at the European Lung Cancer Conference (ELCC) in Geneva, Switzerland.

Dr. Oliver Gautschi, a medical oncologist from Lucern Cantonal Hospital in Switzerland, presented the results of the retrospective EURAF cohort study, which included lung cancer patients whose tumours carried specific mutations in the BRAF gene. The study was conducted by a network of European oncologists, without company involvement.

BRAF mutations are commonly seen in melanoma patients, and are found in about 2% of lung adenocarcinomas, Gautschi explains. Several inhibitors of the B-Raf protein, including vemurafenib and dabrafenib, have been developed for use in melanoma patients, however there is currently no approved drug for BRAF-mutant lung cancer.

As a result, experience with B-Raf inhibitors in lung cancer remains limited. “In the current study, we wanted to find out how many patients in Europe received B-Raf inhibitors outside of a clinical trial, and what their outcomes were,” Gautschi says.

The EURAF study gathered information on 35 lung cancer patients who had been identified as carrying BRAF mutations, who were treated with B-Raf inhibitors between 2012 and 2014.

Most of those patients received vemurafenib, some dabrafenib, and one sorafenib. Overall response rate was 53% as measured by the widely used Response Evaluation Criteria In Solid Tumors (RECIST) guidelines. Overall, progression-free survival time in this group was 5 months.

Most patients were pretreated, and not eligible for enrolment in a clinical trial, which means these results are encouraging, the researchers say, although the study’s small size and retrospective nature mean the analysis of the magnitude of benefit should be treated cautiously.

“The bottom line is that clinicians should be sure to test patients for so-called ‘rare’ driver mutations in lung cancer, because individual patients may derive substantial benefit from targeted therapy,” says Gautschi.

Commenting on the findings, Dr David Planchard, pulmonary oncologist at Gustave Roussy in Villejuif, France, said that the results of the trial confirm the benefit of B-Raf inhibitors in BRAF-mutant non-small cell lung cancer. The current trial also confirmed the good tolerance of the drugs with no new side-effects, he said. Planchard and colleagues have presented a separate phase II study in this area with dabrafenib (1).

“This trial is important because due to the low frequency of this mutation in non-small cell lung cancer we will have few trials on this population,” Planchard commented. “The more data we have, the better we understand how important it is to test for the mutation, especially in adenocarcinomas, and to expose mutation-positive patients to a specific B-Raf inhibitor.”

The results also add to growing support for the approval of B-Raf inhibitors for use in lung cancer, Planchard added. This is important because the rarity of this mutation means that performing the kind of randomized phase III trials usually required for licensing approval will be extremely difficult, he noted.

Looking ahead, it will also be important to see results of combination therapy with inhibitors of B-Raf and a related protein, Mek, in non-small cell lung cancer carrying BRAF-V600E mutations, the researchers note, as this combination has shown a higher clinical benefit in BRAF-mutant melanoma.
-END-

Notes to Editors

1. www.esmo.org/Conferences/Past-Conferences/ESMO-2014-Congress/Press-Media/Promising-Results-Shown-with-Targeted-Approaches-in-Subsets-of-Non-Small-Cell-Lung-Cancer

Abs. 98O_PR Targeted therapy for BRAF-mutant lung cancer: Results from the European EURAF cohort study  O. Gautschi, CH
To be presented at ELCC 2015 on 17.04.2015 from 09:00-10:30  Advanced NSCLC: Proffered Paper Session

8. Promising Clinical Activity Observed With Novel EGFR Inhibitor in Patients With Advanced NSCLC

The highly selective EGFR inhibitor AZD9291 continues to show promising clinical activity in concert with tolerable toxicities in patients with advanced non-small-cell lung cancer (NSCLC) that harbour an acquired EGFR T790M resistance mutation.

Dr Pasi J&#228;nne, Director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute, presented updated results from the phase I AURA study during the Advanced NSCLC Proffered Papers session at the European Lung Cancer Conference, held April 15-18, 2015 in Geneva, Switzerland.

AZD9291, an irreversible inhibitor of EGFR and T790M mutations that also has reduced affinity for wild-type EGFR, was administered to patients with advanced NSCLC experiencing disease progression after treatment with an EGFR inhibitor.

Acquired resistance to EGFR inhibitors has been associated with a secondary EGFR mutation, EGFR T790M, in about 60% of patients.

In the AURA phase I study, 283 patients with EGFR-mutant advanced NSCLC received treatment with AZD9291 at doses ranging from 20 to 240 mg once daily. Patients with stable brain metastases were not excluded from the study. The median patient age was 60; 62% of patients were female, 61% were Asian, and 31% were Caucasian.

Prospective T790M testing was optional for 31 patients enrolled in a dose escalation cohort, but required for 252 patients in the expansion cohort; 163 patients had T790M positive tumours by central testing.

Primary and secondary endpoints met in AURA study

Responses by RECIST v1.1 criteria were observed at all dose levels; the investigator-assessed confirmed overall response rate (ORR) was 59% for patients with EGFR T790M-positive tumours and the ORR was 23% in patients with T790M-negative tumours.

When tumour response was evaluated by investigators in the cohort receiving recommended phase II 80 mg dose of AZD9291 orally, ORR was 66%. The median duration of response had not been reached at the time of analysis, with the longest duration of response being greater than 8 months in patients with EGFR T790M-positive tumours. While also immature, the median progression-free survival (PFS) in this cohort was 10.9 months. The independent centrally reviewed data showed that in patients with EGFR T790M-positive tumours receiving 80 mg daily of AZD9291, ORR was 54%, immature achieved median duration of response was 12.4 months and immature median PFS was 13.5 months.

The most common adverse events with AZD9291 treatment were primarily low-grade diarrhoea and rash that was reported by 50% and 46% of patients, respectively. Grade 3/4 investigator determined treatment related adverse events occurred in 17% of patients.

Prof. Kenneth O’Byrne of the Princess Alexandra Hospital and Queensland University of Technology, Brisbane, Australia & Trinity College, Dublin, Ireland, who discussed the study results, said that currently available EGFR TKIs have two important limitations: 1. wild-type inhibition results in cutaneous toxicity and diarrhoea; 2. efficacy is limited by emergence of the EGFR T790M resistance mutation in approximately 60% of patients.

Third generation EGFR TKIs (AZD9291 and CO1686) are mutation specific inhibitors that inhibit T790M as well as the classical mutations and represent potential strategy to overcome resistance. Phase III studies of novel EGFR TKIs, with less toxicity, in first-line setting are under-investigation. However, Prof. O’Byrne questioned what next after resistance to third-generation TKIs develops and underlined the importance of tissue and liquid biopsies.

Conclusions

According to the investigators, the promising response rate and duration of response results from this phase I study warrant further investigation of AZD9291 and suggest that AZD9291 may have clinical benefit for patients with advanced NSCLC and acquired resistance to EGFR-TKI.

Patients tolerated the agent well and the most frequently occurring toxicities, diarrhoea and rash, were mostly mild and low-grade.

Reference

LBA3. A phase I study of AZD9291 in patients with EGFR-TKI-resistant advanced NSCLC – Updated progression free survival and duration of response data.  

9.  Safety and Efficacy Results with Selected Doses From a Phase I/II Trial of AP26113 in Patients with Advanced Malignancies, Including ALK–Positive NSCLC

AP26113, an inhibitor of anaplastic lymphoma kinase (ALK) that can be taken orally, showed clinical activity at each of three selected dose levels in patients with advanced ALK-rearranged non-small-cell lung cancer (NSCLC) who demonstrated similar response rates across all dose levels that were evaluated.

European Lung Cancer Conference 2015: Abstract 99O
Progression-free survival (PFS) with brigatinib by selected dosing regimens in ALK+ NSCLC patients in a phase 1/2 trial. Median PFS was 12.9 month for 90 mg qd (n=14), not reached for 90 mg qd escalated to 180 mg qd after 7 days (90→180 mg qd; n=26), and 11.1 month for 180 mg/d (n=25).
&#169; Rafael Rosell
Lead investigator, Dr Rafael Rosell, Medical Oncology Service, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain, presented findings from a phase I/II study of AP26113 during the Advanced NSCLC Proffered Papers session at the European Lung Cancer Conference, 15-18 April  2015 in Geneva, Switzerland.

AP26113 is an investigational oral ALK inhibitor that has demonstrated preclinical activity against both native ALK and a broad range of crizotinib-resistant mutants.

The findings from this phase I/II study guided dose selection to be used for testing in the phase II ALTA (ALTA: ALK in Lung Cancer Trial of AP26113) trial of AP26113 in patients with advanced ALK-positive NSCLC.

This single-arm, multicentre study evaluated AP26113 at total daily oral doses that ranged from 30 to 300 mg in patients with advanced malignancies. Prof. Rosell presented findings from the efficacy and safety analysis of AP26113, which was administered to three cohorts of patients at daily doses of 90 mg (90 mg cohort), 90 mg escalating to 180 mg after 7 days (90–180 mg cohort), or 180 mg (180 mg cohort, which included patients receiving 90 mg bid).

By 4 August 2014, the trial had enrolled 137 patients; 79 patients had ALK-positive NSCLC and 71 (90%) of these patients had received prior treatment with crizotinib.

Similar response rates to AP26113 observed across all dose level cohorts

The overall response rate in 60 evaluable patients was 79%, 81%, and 68% in the 90 mg, 90 to 180 mg, and 180 mg cohorts, respectively. Of the 14 patients receiving AP26113 at 90 mg, no complete response (CR) was seen; 11 (79%) patients had a partial response (PR), 1 (7%) patients had stable disease (SD) and progressive disease (PD) was seen in no patients.

In the 26 patients receiving AP26113 in the 90 to 180 mg cohort, 3 (12%) patients had CR, 18 (69%) patients achieved PR, 2 (8%) had SD and PD was observed in one (4%) patient.

In 25 patients receiving AP26113 in the 180 mg cohort, there were two (8%) CR, 15 (60%) PR, 3 (12%) patients had SD, and PD was observed in 5 (20%) patients.

Progression-free survival (PFS) was median 12.9 month in patients receiving the lowest dose of AP26113. Median PFS had not been reached in the 90 to 180 cohort and the median PFS in patients in the 180 mg cohort was 11.1 month.

The most common adverse events (AEs) were mostly grade 1 or 2 and included nausea, diarrhoea, and fatigue, these were reported by patients across all three respective dose cohorts. AEs of grade ≥3 included increased lipase, neoplasm progression and increased amylase.

Events included dyspnoea, hypoxia, and new pulmonary opacities suggestive of pneumonia or pneumonitis occurred within 7 days of starting brigatinib (usually within 24–48 hours), required medical intervention and occurred at lower rates with lower doses. Early-onset pulmonary symptoms were observed in 4% of patients in the 90 mg cohort and in 14% of patients receiving 180 mg. None of the patients receiving the 90 mg dose that was escalated to 180 mg demonstrated early-onset pulmonary symptoms.

Dr Rafal Dziadziuszko of the Medical University of Gdańsk in Poland, who discussed the study results, said that resistance to ALK inhibitors in half of the cases is related on ALK dependence, and in other half to other pathways. He reviewed non-ALK targets of second generation ALK inhibitors and said that it might be necessary to perform a molecular testing at progression to first generation ALK inhibition therapy and then administer the second generation inhibitor. The open questions to be addressed in the future are: drug activity, particularly in the CNS and coverage of resistance mechanisms, toxicity profile and cost issue.

Conclusions

The efficacy of AP26113 was similar at daily doses of 90 mg and 180 mg in patients with advanced ALK-positive NSCLC. However, early-onset pulmonary symptoms were less frequent in the cohorts receiving AP26113 at doses of 90 mg and 90 mg escalated to 180 mg than in patients receiving 180 mg AP26113.

The investigators advanced the oral dose levels of 90 mg daily and 90 mg escalated to 180 mg daily for evaluation in the phase II ALTA trial of AP26113 in ALK-positive NSCLC patients who are resistant to crizotinib.

Reference

99O Phase 1/2 study of AP26113 in patients (Pts) with advanced malignancies, including anaplastic lymphoma kinase (ALK)–positive non-small cell lung cancer (NSCLC): Analysis of safety and efficacy at selected phase 2 doses

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AstraZeneca announces updated progression free survival data for investigational non-small cell lung cancer medicine AZD9291

Friday, 17 April 2015

Late breaking data presented at European Lung Cancer Congress 2015 shows delay in disease progression of over a year

AstraZeneca today announced latest data from the ongoing AURA study of AZD9291 in patients with advanced epidermal growth factor receptor mutation positive (EGFRm) non-small cell lung cancer (NSCLC), who also have the T790M resistance mutation. The data demonstrated a median progression free survival (PFS) of 13.5 months (95% confidence interval (CI) 8.3 months to not calculable (NC))1. These PFS findings relate to independently reviewed data from 63 patients with T790M tumours treated with AZD9291 at a dose of 80mg per day, and are based on only 38% of patients having tumour progression.

The updated data also show an overall response rate with AZD9291 80mg of 54% (95% CI 41% to 67%) and a median duration of response of 12.4 months (95% CI 8.3 months to NC).

Presenting the latest analysis at the European Lung Cancer Conference (ELCC) 2015 in Geneva, Switzerland, AURA principal investigator Dr Pasi A. J&#228;nne MD, PhD, Director, Lowe Center for Thoracic Oncology Dana-Farber Cancer Institute and Professor of Medicine Harvard Medical School, emphasised the sustained activity of AZD9291 as indicated by the key parameters of patient response: “There are few treatment options currently available for patients with advanced EGFRm non-small cell lung cancer who experience disease progression due to a second mutation known as T790M. Management is usually limited to chemotherapy or re-challenge with EGFR tyrosine kinase inhibitors. As AURA continues to mature, and the trend in progression free survival and durable clinical response is maintained, this may support the potential for AZD9291 as a future treatment option for advanced EGFRm NSCLC.”

AZD9291 is a once daily, selective, irreversible EGFR tyrosine kinase inhibitor (TKI) designed to target both the activating sensitising mutation, EGFRm, and T790M, the genetic mutation responsible for EGFR TKI treatment resistance in up to approximately two-thirds of cases of EGFRm advanced NSCLC. There are currently no treatments specifically approved for patients with EGFRm T790M advanced NSCLC.

Antoine Yver, Head of Oncology, Global Medicines Development, AstraZeneca, said: “We are committed to developing novel medicines that address the significant unmet need in lung cancer by focusing on the genetic drivers underlying the disease. We are on track for a regulatory submission of AZD9291 in the US in the second quarter of this year. Our extensive clinical research programme is also investigating the potential of AZD9291 in earlier disease and in combination with other pipeline assets including immuno-oncology molecules. With this comprehensive approach, our goal is to develop a broad range of potential treatment options for patients with EGFR mutation positive non-small cell lung cancer.”

The ongoing AURA Phase I/II study is investigating AZD9291 in patients with advanced NSCLC and disease progression following treatment with an EGFR TKI. As of 2 December 2014, 283 patients with EGFRm advanced NSCLC and acquired resistance to EGFR TKIs were enrolled – 31 patients in dose escalation and 252 patients in expansion cohorts. Of these patients, 163 had T790M tumours confirmed by central testing1. The updated results presented at ELCC build on previously reported data presented at the European Society for Medical Oncology 20142.

In patients treated with AZD9291 80mg, the most common all-cause adverse events (AEs) of any grade were rash, 38% (0% Grade ≥3) and diarrhea, 36% (1% Grade ≥3). Investigator-determined treatment-related Grade ≥3 AEs occurred in 14% of patients.

As of 19 March 2015, of more than 1000 patients across all studies dosed with AZD9291, interstitial lung disease (ILD) grouped term events were reported in approximately 2.7% of patients (27 events): 12 common terminology criteria for adverse events (CTCAE) grade 1–2; 13 grade ≥3; 2 currently ungraded. Of these, a total of 3 patients were reported to have died due to ILD (Grade 5).

AstraZeneca is currently also investigating AZD9291 as first line therapy for EGFRm NSCLC patients, and in combination with MEDI4736 (anti-PDL1 immunotherapy), selumetinib (MEK inhibitor) and AZD6094 (MET inhibitor) in NSCLC. Initial data will be presented at the American Society of Clinical Oncology (ASCO) annual meeting 2015.