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Ben J Solomon
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MA 04 - Advocacy: Listen to the Patients (ID 655)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Patient Advocacy
- Presentations: 1
- Moderators:Rudolf M Huber, C.L. Dégi
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 313 + 314
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MA 04.06 - Developing a Lung Cancer Clinical Quality Registry Framework to Collect Longitudinal Patient-Reported Outcomes (ID 8197)
11:30 - 11:35 | Author(s): Ben J Solomon
- Abstract
- Presentation
Background:
When captured by psychometrically-sound patient-reported outcomes measures (PROMs), patients’ appraisals of their symptoms, quality of life and functional status can provide powerful data to better inform clinicians about the impact of health conditions and the consequences of medical care. Reviewing and reporting on integrated PROMs alongside clinical data may translate to health service improvements and efficiencies. There are, however, many challenges including the need to find sustainable and cost-efficient methods for the routine collection of PROMs across the whole patient journey. This two-phase study set out to develop a lung cancer clinical quality registry framework to collect longitudinal patient-reported outcome measures. Phase 1 focused on the development of the data collection framework and phase 2 sees a 12-month implementation and mixed-method evaluation of the feasibility of implementing the framework. We will report on development of the framework and provide preliminary results on the implementation phase.
Method:
The development phase utilised a formative evaluation method to decide on essential aspects of the PROMs framework. Specifically, a Delphi process was employed to seek consensus on PROMs to administer and the schedule of assessments, with a specific focus on clinical relevance and feasibility of administration. The first Delphi round consisted of individual interviews with lung cancer clinical experts to generate a list of domains to be included in the PROMs. In the second round, aggregated results were presented to the panel and domains of interest were considered alongside PROMs meeting minimum measurement standards. Then, four patients previously treated for lung cancer were invited to provide feedback on the content of PROMs and data collection methods.
Result:
From Delphi findings, it was determined that the EORTC QLQ-C30 and the lung cancer-specific module (QLQ LC13) would be administered at baseline and two, six and 12 months after baseline, and a brief social isolation measure (PROMIS) would be administered at baseline only. A clearly defined subset of patients about to commence chemo-radiation treatment for lung cancer was chosen for the implementation phase and commenced on October 31 2016. To date, 74% (14/19) of eligible patients have been recruited thus far. Preliminary data indicate high adherence to baseline assessments (100%). Adherence is much lower at two months (50%), with non-adherence frequently due to side effects or ill health (38%).
Conclusion:
Identifying and deciding which PROMs to collect, the overall purpose of PROMs collection, data completeness and utility requires careful consideration and evaluation to determine framework sustainability.
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MA 18 - Global Tobacco Control and Epidemiology II (ID 676)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Epidemiology/Primary Prevention/Tobacco Control and Cessation
- Presentations: 1
- Moderators:H. Kawai, Christian Klaus Manegold
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 511 + 512
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MA 18.12 - Quality of Data Informing Epidemiological Studies in Patients with Lung Cancer (ID 7550)
17:00 - 17:05 | Author(s): Ben J Solomon
- Abstract
- Presentation
Background:
Epidemiological studies commonly use data from clinical (i.e. medical records) and administrative (i.e. claims data) datasets for the purposes of exploratory analyses, as well as clinical and quality reporting, benchmarking, risk adjustment, and machine learning. Validity is contingent on accurate and detailed reporting of data, demanding robust methodological validation.
Method:
Single centre retrospective comparative study assessing completeness and agreement (kappa-statistic (κ)) of data reporting for key prognostic variables across three independent data sources, among patients with lung cancer. The study population was formed by random selection of patients from an Australian single centre prospective study. Prospectively collected research study-data (SD) was extracted, and then compared to data extracted from individual patient medical records (MR) as well as International Classification of Diseases (ICD) coding from administrative data (AD).
Result:
The study population included 10% of patients from an Australian lung cancer cohort (n=111/1090), and represented the overall cohort in terms of patient demographics and disease characteristics. Prognostic data for stage, comorbidities, smoking history, performance status, and weight loss at diagnosis, was reported for >96% of patients in SD. Comparatively, AD did not report any prognostic data for 42% (47/111) of patients treated in ambulatory settings, and indeed when reported was grossly inaccurate. By way of examples, according to AD, 23% of patients had ≥1 comorbidity versus 68% by MR and 64% by SD; 38% had positive smoking history versus 78% by MR and 81% by SD; 2% had respiratory comorbidity versus 28% by MR and 37% by SD. Similar patterns were observed for other comorbid conditions. Complete TNM staging was captured in only 45% of MR at the time of first treatment, although with good concordance with SD (κ=0.9, 95%CI 0.7, 1.0). Equally when factors were documented in MR they were reasonably concordant with SD: smoking status (completeness 96.4%, κ=0.9, 95%CI 0.8, 1.0), performance status (completeness 82.0%, κ=0.5, 95%CI 0.4, 0.7) and weight loss (completeness 71.1%, κ=0.3, 95%CI 0.1, 0.5).
Conclusion:
Poor capture of factors (either omission or inaccuracy) limit the potential contribution of both MR and AD for use in clinical, epidemiological, and machine learning research – particularly when being utilised to derive diagnostic, prognostic and classification systems. Use of this data for purposes other than intended may misinform estimates of comorbidity disease burden and fail to appropriately adjust for competing mortality risks in models that inform outcomes reporting and ensuing policy decisions.
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OA 05 - Next Generation TKI (ID 657)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:James Chih-Hsin Yang, Fiona Blackhall
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 301 + 302
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OA 05.06 - Phase 2 Study of Lorlatinib in Patients with Advanced ALK<sup>+</sup>/ROS1<sup>+</sup> Non-Small-Cell Lung Cancer (ID 8573)
16:40 - 16:50 | Presenting Author(s): Ben J Solomon
- Abstract
- Presentation
Background:
Lorlatinib, a selective, potent, brain-penetrant ALK/ROS1 TKI, is active against most known ALK kinase domain mutations. In phase 1 of this ongoing study (NCT01970865), lorlatinib displayed robust clinical activity among patients with ALK[+]/ROS1[+] non-small-cell lung cancer (NSCLC), most of whom were heavily pretreated and had CNS metastases. Phase 2 evaluated efficacy (overall and intracranial), according to prior treatment, and safety at the recommended phase 2 dose (100 mg QD).
Method:
Patients with NSCLC ± asymptomatic CNS metastases enrolled in 6 cohorts (EXP1–5, ALK[+]; EXP6, ROS1[+]). The primary endpoint was objective response rate (ORR) and intracranial ORR by independent central review. Safety, patient-reported outcomes and molecular profiling were also assessed.
Result:
As of 15-March-2017, 227 ALK[+] patients were evaluated for ORR (Table), including 140 with CNS involvement who were evaluated for intracranial ORR.
Of 219 ALK+ patients analyzed for ALK kinase domain mutations at baseline, 46/219 (21%) had ≥1 mutation detected in circulating free DNA; most derived treatment benefit with an ORR of (27/46) 59%. Across all cohorts (N=275), the most common treatment-related adverse events (AEs) and grade 3/4 treatment-related AEs were hypercholesterolemia (81%/16%) and hypertriglyceridemia (60%/16%); 30% and 22% of patients had treatment-related AEs associated with dose interruptions and reductions, respectively. No treatment-related deaths occurred; 7 patients (3%) had treatment-related AEs leading to treatment discontinuation. 157/275 (57%) patients remained on treatment at data cutoff. Most patients reported stable/improved global quality of life (40%/43%).Confirmed ORR Confirmed IC-ORR N n (%) N n (%) ALK[+] cohorts EXP1 (treatment-naïve, no prior ALK-TKIs or CT) 30 27 (90) 8 6 (75) EXP2 (prior crizotinib only) 27 20 (74) 17 10 (59) EXP3 (1 prior ALK TKI ± CT) 59 30 (51) 32 20 (63) EXP3A (prior crizotinib + CT) 32 21 (66) 20 15 (75) EXP3B (any 1 other ALK TKI ± CT) 27 9 (33) 12 5 (42) EXP4 (2 prior ALK TKIs ± CT) 65 27 (42) 45 25 (56) EXP5 (3 prior ALK TKIs ± CT) 46 16 (35) 38 (15 (39) CT, chemotherapy; IC, intracranial.
Conclusion:
Lorlatinib showed clinically meaningful activity, including substantial intracranial efficacy, among ALK[+]/ROS1[+] patients who were either treatment-naïve or failed ≥1 prior ALK TKI. Overall lorlatinib was well tolerated and when needed, AEs were managed by dose delay/reduction or standard medical therapy.
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OA 12 - Emerging Genomic Targets (ID 679)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:H. Akita, Maurice Pérol
- Coordinates: 10/18/2017, 11:00 - 12:30, F203 + F204 (Annex Hall)
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OA 12.06 - Plasma Genomic Profiling and Outcomes of Patients with MET Exon 14-Altered NSCLCs Treated with Crizotinib on PROFILE 1001 (ID 9385)
11:50 - 12:00 | Author(s): Ben J Solomon
- Abstract
- Presentation
Background:
MET exon 14 alterations occur in ~4% of non-squamous non-small cell lung cancers (NSCLCs). Treatment with the MET inhibitor, crizotinib, achieves confirmed and durable responses in patients with MET exon 14-altered NSCLCs, underscoring the need to test for these drivers (as of August 1, 2016, objective response rate was 39% and median duration of response was 9.1 months). Comprehensive molecular tumor profiling is required to detect MET exon 14 alterations that are highly heterogeneous. The utility of plasma profiling to detect these drivers has not previously been explored in a prospective trial.
Method:
Patients with advanced NSCLCs harboring MET exon 14 alterations by local tumor profiling performed in a CLIA-certified or equivalent environment were treated with crizotinib at 250 mg twice daily on an expansion cohort of the ongoing phase I PROFILE 1001 study (NCT00585195). Objective response was assessed by RECIST v1.0. Prospective plasma profiling of circulating tumor DNA (ctDNA) for MET exon 14 alterations was performed using the PlasmaSELECT64 targeted gene panel (sequencing and analysis output by Personal Genome Diagnostics, Boston MA).
Result:
Plasma samples were obtained for MET exon 14 alteration analysis after study amendment approval in 20 of 52 crizotinib-treated patients, of which 18 samples were deemed sufficient for analysis. MET exon 14 alterations were detected in ctDNA in 11 of 18 patients (61% agreement of plasma ctDNA testing with tumor testing) mapping to the same exon 14 splice site region in 10 of the 11 cases. Of the 11 patients with ctDNA-positive tumors, all were evaluable for response. Of these evaluable patients, a confirmed partial response and stable disease were observed in 2 and 4 patients, respectively.
Conclusion:
MET exon 14 alterations can be detected in plasma ctDNA in a subset of patients with advanced NSCLCs that harbor MET exon 14 alterations by tumor testing. Responses to crizotinib were observed in patients with ctDNA-positive testing for a MET exon 14 alteration. Plasma profiling should be considered as an adjunct to tumor profiling in screening patients for MET exon 14 alterations, pending further confirmation.
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 3
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-012 - Ceritinib in Anaplastic Lymphoma Kinase (ALK)+ NSCLC Patients Pretreated With Only Crizotinib: ASCEND-1 Subgroup Analysis (ID 8972)
09:30 - 09:30 | Author(s): Ben J Solomon
- Abstract
Background:
In phase 1 ASCEND-1 study (NCT01283516), ceritinib 750 mg/day (fasted) demonstrated durable whole-body and intracranial responses in both anaplastic lymphoma kinase inhibitor (ALKi)-naïve and ALKi-pretreated patients with ALK-rearranged non-small cell lung cancer (NSCLC). Here, we report the efficacy and safety of ceritinib in patients who were pretreated with crizotinib only from the ASCEND-1 study.
Method:
Patients with ALK+ NSCLC who were enrolled globally received ceritinib 750 mg/day (fasted). Efficacy and safety were evaluated in a subset of patients who had received prior crizotinib only (no other prior antineoplastic therapy). Data cut-off was May 03, 2016.
Result:
Overall, 246 patients with ALK+ NSCLC (83 ALKi-naïve and 163 ALKi-pretreated) received ≥1 dose of ceritinib, of whom, 26 had received prior crizotinib only. Among the 26 crizotinib-pretreated patients, 11 (42.3%) had baseline brain metastases, of which, 7 received prior radiotherapy, 6 (23.1%) had an ECOG performance status of 0, and 24 (92.3%) patients had stage IV disease. The median time from initial diagnosis to ceritinib initiation was 10.5 months (range, 2.4-33.0). At data cut-off, the median duration of exposure (range) was 41.0 weeks (2.9-180.4). In the 26 crizotinib-pretreated patients, per investigator assessment, the overall response rate was 65.4% (95% confidence interval [CI]: 44.3, 82.8), and the disease control rate was 80.8% (95% CI: 60.6, 93.4) (Table). The most frequently reported grade 3/4 adverse events (AEs), regardless of study drug relationship, were ALT increased (30.8%), AST increased (15.4%), diarrhea (11.5%), nausea (7.7%), fatigue (7.7%), and blood alkaline phosphatase increased (7.7%). All 26 patients discontinued treatment due to disease progression (n=12), consent withdrawal (n=6), AEs (n=2), administrative problems (n=4), or death (n=2).
*Median value derived from summary statistics; **Median value estimated by Kaplan-Meier method.Investigator Assessment N=26 Blinded Independent Review Committee Assessment N=26 Best overall response Complete response (CR), n (%) 1 (3.8%) 1 (3.8%) Partial response (PR), n (%) 16 (61.5%) 15 (57.7%) Stable disease (SD), n (%) 4 (15.4%) 5 (19.2%) Progressive disease (PD), n (%) 2 (7.7%) 1 (3.8%) Unknown, n (%) 3 (11.5%) 4 (15.4%) Overall response rate (ORR), % [95% CI] 65.4% [44.3-82.8] 61.5% [40.6-79.8] Disease control rate (DCR), % [95% CI] 80.8% [60.6-93.4] 80.8% [60.6-93.4] Median time to response*, weeks [95% CI] 6.1 [5.1-23.6] 6.4 [5.1-14.0] Median DOR**, months [95% CI] 8.3 [4.2-11.2] 8.5 [3.0-13.6] Median PFS**, months [95% CI] 8.5 [5.3-9.9] 8.2 [4.4-15.2]
Conclusion:
Ceritinib demonstrated durable efficacy in crizotinib-pretreated patients with ALK-rearranged NSCLC. Safety was consistent with the overall ASCEND-1 study population.
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P1.01-016 - Next-Generation Sequencing Shows Mechanisms of Intrinsic Resistance in ALK-Positive NSCLC Patients Treated with Crizotinib (ID 9514)
09:30 - 09:30 | Presenting Author(s): Ben J Solomon
- Abstract
Background:
Crizotinib (XALKORI®) is a small molecule ALK, ROS1, and c-MET tyrosine kinase inhibitor approved for the treatment of patients with ALK-positive or ROS1-positive metastatic NSCLC. PROFILE 1005 was a single arm phase 2 study of the safety and efficacy of crizotinib in previously treated patients with advanced NSCLC that is ALK-positive as determined by the investigational use only FISH test or on a case-by-case basis using a local FISH, IHC or RT-PCR laboratory developed test. In this study 54.1% of patients exhibited a confirmed complete or partial response to crizotinib (responders) by investigator assessment, while 9.9% had a best overall tumor response of progressive disease (progressors). The objective of this analysis was to investigate mechanisms of intrinsic resistance to crizotinib by comparing progressors with responders through a targeted cancer gene panel of next-generation sequencing (NGS).
Method:
Archival tumor tissue used to screen patients for enrollment was analyzed using the FoundationOne NGS panel (Cambridge, MA). Results of the analyses from tumor tissue positive by ALK FISH were compared for a subgroup of progressors (N=22) with a randomly selected subgroup of responders (N=25).
Result:
There was a higher proportion of patients who were ALK-negative by NGS in progressors (8 of 22; 36%) as compared to responders (3 of 25; 12%) (p=0.083), including 5 patients with oncogenic driver mutations in KRAS (G12S, Q61H, amp), EGFR (L858R) and BRAF (G469A). Among responders, 4 patients (16%) had non-EML4 ALK fusions (KIDINS220, EDC4, DTWD2, AFF2) while no such case was detected in progressors. TP53 mutations were detected in 10 progressors (45%) and 5 responders (20%) (p=0.115). Excluding NGS-negative patients, TP53 mutations were detected in 7 of 14 progressors (50%) and 3 of 22 responders (13%) (p=0.026).
Conclusion:
In the small percentage of patients with ALK-positive NSCLC with a best response of progression upon treatment with crizotinib, a higher proportion are ALK-negative by NGS, representing either a technical false-positive or an accurate FISH result reflecting a non-activating gene rearrangement that is not detected by NGS. TP53 mutations were observed at a higher frequency in progressors than in responders in patients with ALK-positive NSCLC by both FISH and NGS. Both technical and biologic factors thus may contribute to apparent intrinsic resistance in patients with ALK-positive NSCLC treated with crizotinib.
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P1.01-033 - Thrombogenic Biomarkers in Patients with NSCLC – Associations with Thrombosis, Progression, and Survival (ID 8852)
09:30 - 09:30 | Author(s): Ben J Solomon
- Abstract
Background:
For patients with NSCLC, the risk of thromboembolism (TE) is high but heterogeneous. We aimed to profile biomarkers among NSCLC patients receiving anticancer therapy to identify patients and time periods of high TE risk where intervention with proven preventative strategies is likely to achieve maximal benefit.
Method:
We assessed the association between baseline biomarker levels and longitudinal biomarker changes, with subsequent incidence of TE (venous (VTE) or arterial (ATE)), disease progression and overall survival. Biomarkers (thromboelastography, d-dimer, fibrinogen, haemoglobin, white cell count, platelet count, neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR)) were sequentially assessed at commencement of anticancer therapy (baseline), weeks 1, 4 and 12, and 3-monthly until 12 months.
Result:
During study follow-up (median 22 months, range 6-31), 129 patients were sequentially assessed over median 5 time points (range 1-9). Patients underwent surgery (n=12), chemo-radiotherapy (CRT, n=47), palliative chemotherapy (CHT, n=36), and single modality radiotherapy (RT, n=34) – only surgical patients received thromboprophylaxis. 24 patients (19%) had documented TE, 19 (15%) VTE and 5 (4%) ATE; 79% occurred within the first 6 months with median time to TE 48 days (range 1-151). Among ambulatory patients (CHT/CRT/RT), an initial model identified as high TE risk those patients with baseline fibrinogen ≥4g/L and d-dimer ≥0.5mg/L, or d-dimer ≥1.5mg/L. Hazard ratio (HR) for TE was 8.0 (p=0.04) for high versus low risk CHT/CRT patients and 6.5 (p=0.07) for high versus low risk for CHT/CRT/RT patients. Comparatively, using an established risk score, HR for TE with Khorana score ≥3 vs. <3 was 1.3 (p=0.68) for CHT/CRT and 1.1 (p=0.91) for CHT/CRT/RT. Considering temporal changes (d-dimer ≥1.5mg/L at week 4), risk assessment was enhanced with 100% sensitivity and 34% specificity for CHT/CRT. Specificity reduced to 27% when including RT patients. NLR, PLR and platelet count were not associated with TE. High TE risk patients (Fib≥4 + d-dimer ≥0.5, d-dimer ≥1.5) also had increased risk of cancer progression (HR 2.3, p<0.01) and mortality (HR 2.5, p<0.01). Baseline NLR≥2.5 and platelet count ≥350 were associated with progression (HR 2.0, p=0.01 and HR 2.0, p<0.01 respectively) and mortality (HR 2.6, p=0.01 and HR 1.9, p=0.01 respectively); PLR was not.
Conclusion:
For ambulatory patients with NSCLC, d-dimer and fibrinogen were associated with TE, cancer progression, and prognosis and could easily be applied in a simple algorithm, for real-time decision-making. In spite of low specificity, consideration of thromboprophylaxis is warranted for high risk patients given substantial TE-associated adverse clinical and economic consequences.
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P1.02 - Biology/Pathology (ID 614)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.02-071b - SASH1 Is a Prognostic Indicator and Future Target in NSCLC (ID 9591)
09:30 - 09:30 | Author(s): Ben J Solomon
- Abstract
Background:
Lung cancer is the most commonly diagnosed cancer in the world and the fifth most common in Australia, where it is responsible for almost one in five cancer deaths. SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor functioning to control of apoptosis and cellular proliferation. Previously SASH1 has been shown to be down-regulated in approximately 90% of lung cancers, however little is known about the role of SASH1 in the pathogenesis of the disease. Cytotoxic platinum based chemotherapy two-drug regimens remain a cornerstone NSCLC patient care, however, resistance to these agents is almost inevitable. The re-sensitisation of these cancer cells to chemotherapeutics is a key to improving patient survival. We hypothesised that modulation of SASH1 expression may alter cisplatin sensitivity.
Method:
A panel of lung cancer cell lines depleted of SASH1 (siRNA) or overexpressing SASH1 were analysed for protein levels via immunoblotting, cell proliferation, and survival/death assays. Treatment of lung cancer cells with the SASH1 protein stabilising compound chloropyramine (0-50 μM) and/or cisplatin (0-10 μM) was performed followed by immunoblotting for SASH1, cell proliferation, and survival/death assays. SASH1 IHC staining of adenocarcinoma and Squamous cell carcinomas was correlated with patient survival.
Result:
We demonstrated that SASH1 depletion results in a significant increase in cellular proliferation of NSCLC cancer cells. The depletion of SASH1 within lung cancer cell lines was associated with a significant increase in cisplatin resistance. Transfection of SASH1 into NSCLC cell lines induced cell death. The treatment of cells with the SASH1 protein stabilising compound chloropyramine increased SASH1 levels, reduced proliferation and induced apoptosis. Furthermore, chloropyramine increased cisplatin sensitivity. The relationship between SASH1 protein expression with overall survival was accessed in a NSCLC TMA panel. This showed that high SASH1 protein levels were associated with a poor prognosis in adenocarcinomas but were non-prognostic in squamous cell disease. Interestingly high SASH1 mRNA levels were associated with a favourable prognosis in adenocarcinoma but were not prognostic in squamous cell cancer. In a panel of cancer cell lines we observed no correlation between mRNA and protein levels that may explain this discrepancy.
Conclusion:
Agents that upregulate SASH1, or SASH1 gene therapy, are potential novel approaches to the management of NSCLC. Further preclinical and clinical studies of chloropyramine in combination with chemotherapy are justified in NSCLC.
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P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-044 - OSCILLATE - Phase 2 Trial of Alternating Osimertinib with Gefitinib in Patients with EGFR-T790M Mutation Positive Advanced NSCLC (ID 9711)
09:30 - 09:30 | Presenting Author(s): Ben J Solomon
- Abstract
Background:
Activating mutations of the epidermal growth factor receptor (EGFR) are key drivers of non-small cell lung cancer (NSCLC) in approximately 10-15% of Western patients and 30-35% of Asian patients. Patients with common activating mutations (L858R and del19) typically have objective tumour response rates (OTRR) of 56-74% and median progression free survival (PFS) of 9-13 months with first-generation EGFR tyrosine kinase inhibitors (TKI) such as erlotinib or gefitinib. The most common mechanism of acquired resistance to first generation EGFR TKI is the T790M mutation (50-60% of cases). Osimertinib is an irreversible EGFR TKI effective against the T790M resistance mutation with OTRR of 51-71% in T790M positive disease. However, acquired resistance invariably develops, and median PFS is approximately 10 months. Mechanisms of resistance include C797S mutations and loss of T790M. Novel strategies that prevent or delay resistance to osimertinib are likely to enhance its durability of response and clinical benefit in EGFR-T790M positive NSCLC.
Method:
DESIGN: Open-label, single arm, multi-centre, phase 2 trial with safety run in. ELIGIBILITY: Adults with advanced, EGFR mutated NSCLC, acquired resistance to first or second generation EGFR TKIs, and mutation of T790M. ENDPOINTS: PFS rate at 12 months, feasibility of alternating osimertinib and gefitinib, time to progression and PFS time, objective tumour response rate, overall survival and adverse events. Tertiary correlative objectives include changes in plasma cfDNA levels for activating EGFR mutations and T790M over time, their relationships with OTRR and the mechanism of resistance. TREATMENT: Osimertinib 80mg daily for 8 weeks (2 cycles), then gefitinib 250mg daily for 4 weeks alternating with osimertinib 80mg daily for 4 weeks (i.e. alternating 4 weekly cycles of each drug) until disease progression or prohibitive toxicity. STATISTICS: A total of 45 participants provides 90% power, with a 1-sided type 1 error rate of 10%, to distinguish the observed proportion alive and progression free at 12 months from true rates of 45% (not worthy of pursuit) and 65% (worthy of pursuit) using a Simon, 2-stage, minimax design allowing for 4 ineligible or inevaluable participants. ASSESSMENT: CT scans 8-weekly until disease progression. Plasma collections at baseline and at the start of each 4-week cycle. OSCILLATE is an investigator-initiated cooperative-group trial led by ALTG, in collaboration with NHMRC Clinical Trials Centre, University of Sydney, with support from Astra-Zeneca.
Result:
Section not applicable
Conclusion:
Section not applicable
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P3.13 - Radiology/Staging/Screening (ID 729)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.13-003 - The Lung Cancer Prognostic Index – a Risk Score to Predict Overall Survival after the Diagnosis of Non-Small Cell Lung Cancer (ID 7551)
09:30 - 09:30 | Author(s): Ben J Solomon
- Abstract
Background:
Outcomes in Non-Small Cell Lung Cancer (NSCLC) are poor but heterogeneous, even within TNM stage groups. To improve prognostic precision we aimed to develop and validate a simple model for the prediction of overall survival (OS) using patient and disease variables.
Method:
The study population included 1458 patients from three independent cohorts. Associations between baseline variables and OS were estimated in a derivation cohort from a prospective single-centre study (n=695) using Cox proportional hazards regression. Points were allocated to variables based on the strength of association to create the Lung Cancer Prognostic Index (LCPI). Model performance was assessed (by a c-statistic for discrimination and Cox-Snell residuals for calibration) in two independent validation cohorts (n=479 and n=284).
Result:
Three disease-related and six patient-related variables were found to predict OS: stage, histology, mutation status, performance status, weight loss, smoking history, respiratory comorbidity, sex and age. Patients were classified according to predicted LCPI score. Two-year OS rates according to LCPI in the derivation and two validation cohorts respectively were 84%, 77% and 68% (LCPI 1: score≤9); 61%, 61% and 42% (LCPI 2: score 10-13); 33%, 32% and 14% (LCPI 3: score 14-16); 7%, 16% and 5% (LCPI 4: score ≥15). Predictive performance (Harrell’s c-statistics) were 0·74 for the derivation cohort, 0·72 and 0·71 for the two validation cohorts.
Conclusion:
The LCPI contributes additional prognostic information which, in conjunction with other validated tools and evidence based management guidelines, may be applied to counsel patients, guide clinical trial eligibility, or standardise mortality risk for epidemiological analyses.
