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Å. Helland
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-013 - Patient-Reported Outcomes and Safety from the Phase III ALUR Study of Alectinib vs Chemotherapy in Pre-Treated ALK+ NSCLC (ID 9007)
09:30 - 09:30 | Author(s): Å. Helland
- Abstract
Background:
Alectinib demonstrated superior efficacy versus chemotherapy in ALK+ NSCLC after crizotinib failure (ALUR; NCT02604342). We present PROs and safety in the ITT population and in patients with baseline CNS disease (C-ITT).
Method:
Patients (n=107) with pre-treated ALK+ NSCLC (randomised 2:1) received alectinib (600mg BID) or chemotherapy (pemetrexed 500mg/m[2] or docetaxel 75mg/m[2] q3w) until PD/death/withdrawal. Primary endpoint: investigator-assessed PFS. Secondary endpoints: safety and PROs. Symptoms, functioning, and HRQoL were reported using questionnaires: EORTC QLQ-C30; lung module QLQ-LC13; BN-20 (3 items, CNS symptoms). Pre-specified endpoints included time-to-deterioration (TTD) in lung cancer symptoms, longitudinal analyses of mean score changes from baseline, proportion of patients with clinically meaningful change (≥10-point change from baseline) during treatment.
Result:
High compliance with assessment completion (alectinib 91.7%, chemotherapy 88.6% at baseline); compliance remained ≥70% with alectinib, and decreased with chemotherapy (64.3%, Week 6; ≤70% thereafter). Deterioration of patient-reported fatigue (median TTD 2.7 vs 1.4 months) and arm/shoulder pain (median TTD 8.1 vs 1.9 months) was delayed with alectinib versus chemotherapy. Median TTD in composite symptom endpoint (cough, dyspnoea, chest-pain) was similar between arms. Alectinib patients reported improvement in lung cancer symptoms from baseline (least square [LS] mean) during treatment: fatigue (-6.2), single-item dyspnoea (-6.0), multi-item dyspnoea scale (-2.3), coughing (-4.9), chest pain (-4.2), pain in other parts (-5.3). More patients reported improvement in baseline symptoms (nausea/vomiting, diarrhoea, peripheral neuropathy) with alectinib versus chemotherapy, except constipation. More alectinib patients reported improvements in cognitive function versus chemotherapy (ITT 19% vs 3%; C-ITT 24% vs 4%); average change from baseline in cognitive function favoured alectinib (LS means difference 10.0, 95% CI 2.2–17.7). Median treatment duration: 20.1 weeks alectinib (95% CI 0.4–8.2), 6 weeks chemotherapy (95% CI 1.9–47.1). For alectinib versus chemotherapy: AEs leading to discontinuation, 5.7% vs 8.8%; dose reductions, 4.3% vs 11.8%; dose interruptions due to AEs, 18.3% vs 8.8%. AEs: 77.1% alectinib (grade 3–5, 27.1%); 85.3% chemotherapy (grade 3–5, 41.2%); one fatal AE (chemotherapy); grade ≥3 AEs: 41.2% chemotherapy versus 27.1% alectinib. TEAEs occurring in ≥10% patients: constipation (alectinib 18.6%, all grade 1–2; chemotherapy 8.8% [grade ≥3 2.9%]), nausea (alectinib 1.4%, all grade 1–2; chemotherapy 17.6% [grade ≥3 2.9%]) and fatigue (alectinib 5.7%, all grade 1–2; chemotherapy 26.5% [grade ≥3 8.8%]).
Conclusion:
Alectinib improved HRQoL, functioning, and symptom burden versus chemotherapy (except constipation). Safety of alectinib compared favourably to chemotherapy. Alectinib patients (ITT and C-ITT populations) derived benefit versus chemotherapy.
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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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P1.02-028 - Pathways Involved in Early Stage Lung Cancers (ID 9087)
09:30 - 09:30 | Author(s): Å. Helland
- Abstract
Background:
Lung cancer is a heterogeneous disease and we have few good markers of therapy prediction for chemotherapy and even immunotherapy. The biological mechanisms driving the tumour growth of different tumours even within the same histology are likely to vary and cause the diversity in therapy response. Pathifier is an algorithm developed by Eaton Domany’s group (Drier Y et al. PNAS, 2013 ) to estimate the deregulation of pathways of tumour samples based on mRNA expression levels of the genes in the pathway. Briefly, the algorithm estimates the deviation of the pathway in the tumour samples compared with normal samples. We analyse pathways deregulated in early stage squamous cell carcinomas to identify pathways potentially linked to therapy response. Such analyses have been performed for breast cancer (Livshits A et al, MolOnc, 2015), but have so far not been applied to lung carcinomas.
Method:
A total of 198 patients undergoing surgery for squamous cell lung cancer were included in the study. mRNA was extracted from the surgically resected tumour from all patients and from adjacent normal lung tissue from 22 patients. An adjustment of the pathifier algorithm was developed to avoid over-estimation of pathway deregulation. The samples were clustered according to adjusted pathway deregulation. Extensive clinical information such as mutation status, smoking history and survival was available.
Result:
Hierarchial clustering of the adjusted pathway deregulation scores identified separate clusters of squamous cell carcinomas of the lung dominated by different biological pathway with putative difference in clinical behaviour. Based on the biological activity, subgroups of patients are suggested to respond to immunotherapy and cell cycle inhibitors. The clusters are linked with survival, smoking history and expression of immune-related genes including PD-L1.
Conclusion:
Subgroups of lung squamous cell carcinomas have different biology represented by deregulation of groups of pathways. These biological differences can be used to identify clinically relevant markers of prognosis and therapy prediction. The results should be validated in functional studies.
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P2.02 - Biology/Pathology (ID 616)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.02-053 - The Prognostic Value of 18 Circulating Markers of Inflammation, Endothelial Activation and<br /> Extracellular Matrix Remodelling in Non-small Cell Lung Cancer Patients (ID 8302)
09:30 - 09:30 | Author(s): Å. Helland
- Abstract
Background:
The aim of the study was to assess the prognostic value of 18 proteins as markers of inflammation and fibrosis (Table 1) in surgically treated non-small cell lung cancer patients and how the chronic obstructive pulmonary disease (COPD) as co-morbidity affected the prognostic significance.
Method:
Blood samples were collected from 207 lung cancer patients with an early-stage disease before surgery. 55,6% of the lung cancer group had COPD and the majority of these (86%) had moderate COPD (GOLD 2). We grouped the lung cancer patients with moderate, severe and very severe COPD (GOLD 2,3 and 4) in one group, and the lung cancer patients with mild (GOLD 1) or no COPD in another group. Serum levels of 18 proteins were measured by enzyme immunoassays. The proteins were selected because most were previously known to be associated with lung cancer and its prognosis, some with COPD.
Result:
Higher soluble tumour necrosis factor (TNF) receptor type 1 (sTNFR1) level was associated with better overall survival (OS) and progression-free survival (PFS) for lung cancer patients with COPD (OS p=0.006 and PFS p=0.030) and without COPD (OS p=0.040). High level of C-reactive protein (CRP) was significantly associated with poor overall survival regardless of COPD status. Higher osteoprotegerin (OPG) level was significantly associated with better PFS (p=0.014) and OS (p=0.027) in patients with lung cancer and COPD. In lung cancer patients with COPD, only CRP was significantly increased compared to patients without COPD of those three proteins.
Conclusion:
Whereas high levels of sTNFR1 and OPG, members of the TNF receptor superfamily, were associated with better prognosis, high level of CRP was associated with worse prognosis. This illustrates the complex role of inflammation and TNF-related molecules, particularly in the prognosis of non-small cell lung cancer, at least partly influenced by COPD as co-morbidity.
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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: 2
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-035 - Osimertinib in Relapsed EGFR-Mutated Non-Small Cell Lung Cancer Patients with Brain Metastases: Results from the TREM-Study (ID 9286)
09:30 - 09:30 | Author(s): Å. Helland
- Abstract
Background:
Osimertinib, an irreversible EGFR-TKI with activity also against the resistance mutation T790M, has a high brain permeability surmising intracerebral efficacy in T790M-negative cases. We assessed the efficacy of osimertinib in T790M-positive and –negative patients.
Method:
The TREM-study is an investigator initiated phase 2, single-arm, multi-center clinical trial conducted in five Northern European countries. Patients with advanced EGFR-mutated NSCLC with progression after at least one EGFR-TKI were assigned to treatment with osimertinib 80 mg daily until radiological progression or death. Both T790M-positive and –negative patients were enrolled, as well as patients with stable and asymptomatic brain metastases. The primary endpoint was objective response rate (ORR) according to RECIST 1.1. Secondary endpoints were progression free survival (PFS), duration of response (DoR), disease control rate (DCR) and overall survival (OS). We here present data from a subset of patients with brain metastases at study entry.
Result:
Of 147 included patients, 34 presented with CNS-metastases at inclusion. This subset of patients had poorer performance status at baseline than the full study cohort (31 % with ECOG 2 in the CNS-subgroup vs 17 % in the full study cohort) and the median age was lower (61.5 vs 65 years), otherwise similar to the full cohort in terms of baseline characteristics. 69 % (20/29) were T790M-positive and 31 % (9/29) negative. 5 patients had unknown T790M-status. 28 patients were evaluable for response. ORR was 39 % (11/28) and DCR 75 % (21/28). For T790M-positive patients ORR was 53 % (9/17) and DCR 88 % (15/17), in T790M-negatives 13 % (1/8) and 38 % (3/8) respectively. Median DoR in T790M-positive patients was 14.7 months (95 % CI 6.4-22.9) and 5.5 months in one T790M-negative patient. Two patients had ongoing responses after 15.9 and 17.5 months at data cutoff. Median PFS in the CNS-subgroup was 7.2 months (95 % CI 4.1-10.3 months) vs 9.7 months (6.3-13.1) in patients without CNS metastases, p=0.300, regardless of T790M-status. In the CNS-subgroup PFS in the T790M-positive patients was 10.1 months (7.9-12.3) vs 2.0 months (0.9-3.2) in the T790M-negative patients, p<0.001. Of 18 patients who had progressed at cutoff, 7 had CNS as site of progression (4 T790M-negative, 2 unknown and only one T790M-positive).
Conclusion:
Although a limited number of patients in this subgroup analysis, our results show that osimertinib has similar efficacy in patients with CNS disease as without, whereas the benefit in T790M-negative patients may be substantially lower.
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P2.03-037 - Osimertinib in Relapsed EGFR-Mutated, T790M-Negative Non-Small Cell Lung Cancer (NSCLC) Patients: Results from the TREM-Study (ID 9415)
09:30 - 09:30 | Author(s): Å. Helland
- Abstract
Background:
The resistance mutation T790M emerges in around 60 % of EGFR-TKI treated NSCLC patients. Osimertinib is approved only in T790M-positive patients. We assessed the efficacy of osimertinib in both T790M-positive and -negative patients and here present results from T790M-negative patients.
Method:
In this investigator initiated, multicenter, single-arm, phase 2 clinical trial conducted in five Northern European countries, patients with progression on at least one previous EGFR-TKI and with measurable disease by RECIST 1.1 were assigned to treatment with 80 mg of osimertinib daily until radiological progression or death. Rebiopsy for assessment of mutational status was done after inclusion. Plasma samples were collected for translational research purposes (not analyzed yet). The primary endpoint was objective response rate (ORR) according to RECIST 1.1. Secondary endpoints were progression free survival (PFS), duration of response (DoR), disease control rate (DCR) and overall survival (OS).
Result:
T790M-status was assessable in rebiopsies from 120 of 147 included patients. Of these, 42 patients (35 %) were T790M-negative in tissue. 55 % (23/42) of the T790M-negative patients had exon 19 deletion at diagnosis as opposed to 71 % of the T790M-positives, other baseline factors were similar between the two groups. ORR in the T790M-negative group was 19 % (7/36) including one patient with complete response. In the T790M-positive group, ORR was 52 % (37/71), no complete responses. DCR was 64 % (23/36) and 87 % (62/71), respectively. All responses were confirmed. Median DoR was 11.0 months (95 % CI 3.0-19.1) in the negatives and 12.0 months (8.7-15.2) in the positives, p = 0.887. In the T790M-negative group, median PFS was 5.5 months (2.6-8.3) vs 10.8 months (8.2-13.4) in the T790M-positive group, p = 0.009. Subgroup analyses were performed in the T790M-negative group and there was significant higher median PFS in patients without CNS-metastases (5.6 vs 1.6 months, p = 0.007), in patients with duration of previous TKI-treatment over median (15 months) vs under (9.7 vs 3.5 months, p = 0.044) and in patients with one previous line of TKI vs two or more lines (7.3 vs 2.0 months, p = 0.007).
Conclusion:
T790M-negative patients who respond have similar DoR as T790M-positive patients. T790M-negative patients without CNS-metastases and with durable response on first EGFR-TKI could benefit from osimertinib.
