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L. De Petris
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MA07 - ALK-ROS1 in Advanced NSCLC (ID 385)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA07.01 - Updated Pooled Analysis of CNS Endpoints in Two Phase II Studies of Alectinib in ALK+ NSCLC (ID 5354)
11:00 - 11:06 | Author(s): L. De Petris
- Abstract
- Presentation
Background:
Based on two single-arm, multicentre, phase II studies (NP28673 [NCT01801111] and NP28761 [NCT01871805]), the FDA approved the ALK inhibitor alectinib for use in ALK+ NSCLC patients after prior crizotinib. Alectinib was well tolerated in both phase II studies and showed efficacy against both systemic and central nervous system (CNS) disease, the latter being a common progression site in ALK+ NSCLC. This analysis uses pooled data from the latest cut-offs (22 Jan 2016 for NP28761; 1 Feb 2016 for NP28673) to examine the long-term CNS efficacy of alectinib.
Methods:
Both studies enrolled crizotinib-refractory patients ≥18 years with ECOG PS 0–2 and locally advanced or metastatic ALK+ NSCLC (confirmed by FDA-approved test). CNS metastases were permitted if asymptomatic. Patients received 600mg oral alectinib BID. The primary endpoint in both studies was objective response rate (ORR) by independent review committee; secondary CNS endpoints included CNS ORR, CNS duration of response (DoR), and CNS disease control rate (DCR). CNS response and progression were determined by RECIST v1.1. All patients had baseline imaging to assess CNS metastases, with further imaging every 6 or 8 weeks for NP28761 and NP28673, respectively.
Results:
The overall pooled analysis population comprised 225 patients (n=87 from NP28761; n=138 from NP28673); median follow-up for this updated analysis was 18.8 (0.6–29.7) months (>6 months additional follow-up). At baseline, 50 patients had measurable and 86 had non-measurable CNS disease; together, these groups comprised 136 patients, 60% of the overall pooled population. Seventy percent of patients had prior CNS radiotherapy; 58% of these completed radiotherapy >6 months before study entry. Updated CNS data are shown in the Table and are consistent with systemic results.Measurable CNS disease at baseline (n=50) Measurable and non-measurable CNS disease at baseline (n=136) CNS ORR, n (%) [95% CI] 32 (64.0) [49.2–77.1] 60* (44.1) [35.6–52.9] Complete response (CR), n (%) 11 (22.0) 39* (28.7) CNS DCR, n (%) [95% CI] 45 (90.0) [78.2–96.7] 117 (86.0) [79.1–91.4] Median CNS DoR, months [95% CI] Patients with event, n (%) 11.1 [7.6–NE] 18 (56.3) 13.8 [11.0–21.5] 32 (53.3) * N.B. Non-measurable disease response can only be classified as CR, non-CR/non-progressive disease (PD) or PD
Conclusion:
This updated pooled analysis with mature data confirms that alectinib can provide long-term control of CNS metastases in ALK+ NSCLC, with a high CR rate.
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-044 - Educational Level and Management in Small-Cell Lung Cancer (SCLC): A Population-Based Study (ID 4568)
14:30 - 14:30 | Author(s): L. De Petris
- Abstract
Background:
In a previous study we reported that educational level is a prognostic factor in SCLC, with females and LD patients with a higher education having a longer survival. In this study we examined possible associations between educational level, lead times and treatment strategies in the same cohort.
Methods:
The study was based on information in LcBaSe, a lung cancer research database generated by record linkages between the Swedish National Lung Cancer Register and several other population-based registers. Educational level was categorized according to number of years of schooling;low(≤ 9 years), middle (10-12 years), high (≥13 years). Stage was classified as limited disease (LD) and extensive disease (ED). Lead times were defined as A) from first radiological sign of a tumor to definite diagnosis and B) from date of referral from primary care to diagnosis. Treatment groups were divided as; chemotherapy (CT), CT+Radiation Therapy (CT+RT), Palliative RT or no oncological therapy.
Results:
The study population encompassed 4278 patients with a SCLC diagnosis between 2002-2011. Median age was 69 years. 988 (23.1 %) patients were diagnosed with LD (low E: 22.9 %, middle E: 23.6%, high E: 26.7 %) and 3187 (74.5 %) with ED (low E: 74.8, middle E: 74.0 %, high E: 73.3%) .One fifth of patients had a poor performance score (PS 3-4). The median lead time A was 14 days (IQR 5-32 days) and for lead time B 9 days (IQR 3-21 days). There were no differences in lead times between the educational groups. The proportion of patients receiving CT+RT was approximately 80 % in LD (Low E: 78.5% Middle E: 79.2% High E: 82.4 %) and 5 % in ED (Low E: 4.2%, Middle E: 5.3% High E: 6.8%). The percentage of patients receiving CT was 18 % in LD (Low E: 19.7% Middle E: 18.7 % High E: 15.3%) and 82 % in ED (Low E: 81.2 %, Middle E: 83.9 % High E: 81.4 %).
Conclusion:
There were no significant differences between educational groups in lead times or management. We conclude that the prognostic impact of educational status in Swedish SCLC patients does not appear to reflect inequalities in access to the healthcare.
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-013 - Outcome of Patients with ALK+ NSCLC and Brain Metastases in Relation to Disease Burden and Clinical Management (ID 5086)
14:30 - 14:30 | Author(s): L. De Petris
- Abstract
Background:
The management of ALK+ NSCLC patients with CNS metastases represents a clinical challenge. We conducted this single institution retrospective analysis in order to evaluate the frequency of CNS metastases in this patient group and explore clinical features associated with survival
Methods:
Between 2011 and 2016, 70 patients with advanced ALK+ adenocarcinoma were treated at our institution. Data on CNS imaging modality, treatment strategy and outcome was collected by chart review
Results:
CNS imaging was performed with either MRI(36%) or CECT(64%) in 59 cases, and CNS metastases were diagnosed in 56% of examined subjects. The characteristics of these 33 patients were as follows: gender male/female 45%/54%; median age 60y (IQR 50-65); # of CNS metastases 1-3/4-10/>10 21%/36%/42% (including 3 subjects with leptomeningeal involvement); timing for diagnosis of CNS metastases: at primary cancer diagnosis (21%), at PD on chemotherapy (33%), at PD on crizotinib (39%), at PD on 2[nd] generation ALKi (6%). Radiotherapy was administered as either SRS(42%) or WBRT(58%) in 66% of cases. Overall medical treatment was chemotherapy (n=32); crizotinib (n=28); 2[nd] generation ALKi, either alectinib, ceritinib or brigatinib (n=22). The first treatment strategy upon diagnosis of CNS metastases was radiotherapy alone, crizotinib or a 2[nd] gen ALKi in 42%, 24% and 33% of subjects, respectively. In 4 cases, the 2[nd] generation ALKi was started directly after completion of radiotherapy. Median OS from the diagnosis of CNS metastasis was 18 months (95% CI 9-50). 1- and 2-year survival rates were 59% and 44%, respectively. Cox proportional hazard analysis showed that neither gender, age, timing for diagnosis of CNS metastasis nor the use of radiotherapy were significant prognostic factors for OS in this patient cohort. Survival analysis stratified by Number of CNS metastasis showed a trend favoring 1-3 met (median OS 59 months) vs 4-10 and >10 lesions (median OS of 25 and 9 months, respectively), with the three survival curves crossing each other (p=0.1). On the other hand, the first treatment strategy after the diagnosis of CNS metastases was shown to be indeed a significant prognostic factor for OS. Median OS for patients treated with crizotinib, radiotherapy alone or a 2[nd] ALKi (with or without RT) was 9 months, 29 months and Not reached, respectively (p=0.03).
Conclusion:
This retrospective study confirms the high incidence of CNS metastases in Caucasian patients with advanced ALK+ NSCLC. The wider implementation of 2[nd] generation ALKi in clinical practice may change the prognosis of these subjects
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P2.03b-084 - Profiling of Eph Signaling in Malignant Pleural Effusions- Identification of Therapy Approaches and Associated Biomarkers (ID 4573)
14:30 - 14:30 | Author(s): L. De Petris
- Abstract
Background:
For late stage lung cancer (LC) patients few treatment options are at hand and the survival time is very limited, hence novel therapies and associated biomarkers are urgently needed. Erythropoietin-Producing Hepatocellular carcinoma receptor (Eph) tyrosine kinase family and their ligands, Ephrins, drive multiple hallmarks of cancer e.g. proliferation/invasion. The Eph signaling pathways are attractive drug targets due to their dual role in oncogenesis and tumor progression. We analyzed Ephs/Ephrins signaling in LC cells from pleural effusions (PE) to reveal altered kinase pathways and putative BMs. We also assessed cytotoxicity and kinome alterations in PE tumor cells exposed to targeted agents and chemotherapy in vitro.
Methods:
Tumor cells purified from PE, assessed for histology, mutation and translocation status (EGFR, KRAS, BRAF and Alk), were grown in vitro. Toxicity of tyrosine kinase inhibitors (TKIs (e.g. erlotinib, crizotinib, AG1024, AZD9291, dasatinib), EGFR blocker (cetuximab) and/or chemotherapy (e.g. cisplatin, gemcitabine, etoposide) were analyzed after 72 h with the Tox8 assay. Ephs/Ephrins signaling components were studied using western blot, immunoprecipitation and by proximity ligation assay. Mutations and signaling heterogeneity were visualized using padlock probe method. For kinome profiling PathScan RTK signalling antibody array was used.
Results:
PE isolated tumor cells were identified as adenocarcinoma, squamous cell carcinoma and SCLC and their EGFR, KRAS, BRAF and Alk mutational status determined. High levels of Ephrin B3 and phosphorylated EphA2 ser897, previously shown to be instrumental in driving NSCLC proliferation and invasion in vitro, were confirmed and also shown to directly interact, indicating the importance of this signaling event. The G391R mutation in EphA2, which is reported to cause a constitutive activation of EphA2 and to be linked to metastasis, but also mutations in EGFR (G719A, G719S, T790M and L858R) were detected. The PE derived tumor cells were hetereogenous in their survival response to TKIs and chemotherapy. However, cells with ALK translocation were sensitive to crizotinib and EGFR mutated cells showed response to erlotinib, cetuximab, AG1024, AZD9291 and dasatinib. Kinome analysis revealed selective signaling pathways that could also be targeted in combinational drug treatment.
Conclusion:
Screening of PE samples from LC patients for targeted agents alongside aberrant Ephs and kinome signaling, can be used to identify novel drug candidates. Together with frontline kinome profiling of NSCLC clinical specimens upon treatment it provides an opportunity to explore/identify new therapeutics for LC.
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P2.05 - Poster Session with Presenters Present (ID 463)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Radiotherapy
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.05-033 - Predictors of Survival after Whole Brain Radiotherapy for Patients with Brain Metastasized Lung Cancer (ID 4794)
14:30 - 14:30 | Author(s): L. De Petris
- Abstract
Background:
Whole Brain Radiotherapy (WBRT) has been the standard of care for multiple brain metastases, but due to its toxicity and lack of survival benefit, its use in the palliative setting has started to be questioned. New clinical algorithms regarding the correct use of WBRT are needed.
Methods:
This was a retrospective, single institution cohort study, consisting of 280 patients with brain metastasized lung cancer who received WBRT at Karolinska University Hospital between 2010 and 2015. Information about RPA and GPA scores, demographics, histopathological results and received oncological therapy was collected. Predictors of Overall survival (OS) from the time of received WBRT were identified by Cox regression analyses. OS between GPA and RPA classes was compared by pairwise log rank test. A subgroup analysis was performed stratified by RPA class. Separate multivariate analyses were performed for RPA and GPA scoring systems, due to significant collinearity between them.
Results:
Median OS was 324, 130 and 41 days for RPA class 1(n=13), 2(n=165) and 3(n=101), respectively. Median OS for GPA groups 0 (0-1 points, n=168), 1 (1.5-2.5 points, n=98) and 2 (3-4 points, n=13) was 55, 166 and 110 days, respectively. Age>70 years was associated with worse OS. OS differed significantly between RPA class 1 versus 3 and 2 versus 3, GPA groups 0 versus 1 and age (p<0.0001 for all comparisons). Multivariate analyses are shown in table 1.Figure 1
Conclusion:
WBRT should be omitted for RPA class 3 patients. RPA class 1 patients should receive WBRT if clinically indicated. For RPA class 2 subgroup, patients with age≤70 years and GPA≥1.5 points should be treated as RPA 1, whereas patients with age>70 and GPA<1.5 points as RPA 3. WBRT is not recommended in patients older than 70 years and GPA≥1.5 points, and should be considered in younger patients with GPA<1.5 points.
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P3.02a - Poster Session with Presenters Present (ID 470)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02a-016 - Pooled Efficacy and Safety Data from Two Phase II Studies (NP28673 and NP28761) of Alectinib in ALK+ Non-Small-Cell Lung Cancer (NSCLC) (ID 5044)
14:30 - 14:30 | Author(s): L. De Petris
- Abstract
Background:
Alectinib is an FDA-approved ALK TKI, for treatment of patients with ALK+ metastatic NSCLC who have progressed on, or are intolerant to, crizotinib. Systemic and CNS efficacy was demonstrated in two single-arm, phase II studies (NP28673 [NCT01801111] and NP28761 [NCT01871805]). We report the pooled systemic efficacy and safety analysis of alectinib from 2016 cut-offs 22 January, NP28761 and 1 February, NP28673.
Methods:
Patients were ≥18 years, had locally advanced or metastatic ALK+ NSCLC [FDA-approved FISH test] and had progressed on, or were intolerant to, crizotinib. Patients received oral alectinib 600mg twice daily until disease progression, death or withdrawal. The pooled analysis assessed objective response rate (ORR) by an independent review committee (IRC) using RECIST v1.1 (primary endpoint in both studies); disease control rate (DCR); duration of response (DOR); progression-free survival (PFS); overall survival (OS); and safety.
Results:
The pooled dataset included 225 patients, (n=138 NP28673; n=87 NP28761). Median age was 53 years, 60% of patients had baseline CNS metastases and 77% had received prior chemotherapy. The response-evaluable (RE) population by IRC included 189 patients (84%). Median follow-up was 18.8 months (0.6–29.7). In the RE population (n=189) ORR by IRC was 51.3% (95% CI 44.0–58.6; all partial responses), a DCR of 78.8% (95% CI 72.3–84.4), with a median DOR of 14.9 months (95% CI 11.1–20.4) after 58% of events. In patients with prior chemotherapy (n=148), IRC ORR was 49.3% (95% CI 41.0–57.7); DCR: 79.1% (95% CI 71.6–85.3); median DOR: 14.9 months (95% CI 11.0–21.9) after 59% of events. In patients who were chemotherapy-naïve (n=41), IRC ORR was 58.5% (95% CI 42.1–73.7); DCR: 78.0% (95% CI 62.4–89.4); median DOR: 11.2 months (95% CI 8.0–NE) after 54% of events. In the total pooled population (n=225) median PFS by IRC was 8.3 months (95% CI 7.0–11.3) after 69% of events and median OS was 26.0 months (95% CI 21.4–NE) after 43% of events. Grade ≥3 adverse events (AEs) occurred in 40% of patients and the most common were dyspnoea (4%), elevated levels of blood creatine phosphokinase (4%) and alanine aminotransferase (3%). The mean dose intensity was 94.6%. Fourteen patients withdrew due to AEs; 20.9% had AEs leading to dose interruptions/modification.
Conclusion:
This pooled analysis confirmed alectinib has robust systemic efficacy with a durable response in this population and in patients with or without prior chemotherapy. Alectinib had an acceptable safety profile.
