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S.A. Laurie



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    MINI 25 - Trials, Radiation and Other (ID 142)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      MINI25.01 - A Phase II Study of Dovitinib in Previously-Treated Malignant Pleural Mesothelioma: The Ontario Clinical Oncology Group DOVE-M Trial (ID 1302)

      16:45 - 16:50  |  Author(s): S.A. Laurie

      • Abstract
      • Presentation
      • Slides

      Background:
      Following failure of a platinum-antifolate combination regimen, there is no standard therapy for advanced malignant pleural mesothelioma (MPM). The fibroblast growth factor receptor (FGFR) signaling pathways may be a relevant target in MPM. Dovitinib inhibits multiple tyrosine receptor kinases, predominantly the vascular endothelial growth factor receptors (VEGFR), but also FGFR.

      Methods:
      This open-label multicentre phase II trial enrolled consenting adult patients with advanced, histologically-confirmed MPM who had previously received platinum-antifolate combination chemotherapy and up to one additional line of systemic therapy. Patients were ECOG PS < 2 and had adequate end-organ function. Dovitinib was administered orally at 500 mg/day for 5 days on, 2 days off; cycle length was 28 days. Two dose reductions (to 300 mg) for toxicity were permitted. Response was assessed every 2 cycles using RECIST 1.1 criteria modified for MPM. Correlative studies included FGFR-1 amplification on archival tumour and serum samples for circulating angiogenesis factors. Pre- and cycle 1 day 15 on-treatment diffusion-weighted pleural MRI was evaluated for its potential as an early marker of drug effect. The primary end-point was the proportion of patients progression-free at 3 months (PF3). A two-stage design was used: H0: 3-month PFS=40% versus HA: 3-month PFS=65% (roughly corresponding to a median PFS of 4.5 months), with α=0.05, β=0.20. If 6 of 12 PF3 in stage I, an additional 14 patients would be enrolled, with dovitinib of interest if > 15 of 26 PF3.

      Results:
      12 patients (10 males, median age 67) were enrolled. The median number of cycles administered was 2.5 (range 1-8). Commonly observed and / or grade 3 at least possibly related adverse events (any grade / grade 3, %): diarrhea (67 / 0%) vomiting (50 / 0%) fatigue (42 / 8 %), nausea (42 / 8 %), rash (0 / 17 %), syncope / generalized muscle weakness / elevated ALT (0 / 8 % each). No hyperphosphatemia was observed. 7 patients had at least one dose interruption (5 in cycle 1) and 5 had a dose reduction (1 to 300 mg); median dose intensity during cycles 1 and 2 was 80 %. 3 patients discontinued due to clinical progression by day 1 cycle 2. Best response: 1 unconfirmed PR, 4 SD, 2 PD and 4 inevaluable (3 with clinical PD; 1 intercurrent illness). The median PFS was 2.6 months and the median OS was 4 months. PF3 was 50%; although the criterion for proceeding to stage II accrual was met, the trial was halted due to a combination of minimal activity with several early progression events and poor tolerability in this patient population.

      Conclusion:
      Dovitinib has minimal activity and a toxicity profile comparable to other VEGFR inhibitors in previously-treated MPM; it is not clear if FGFR is effectively targeted. Correlative studies are ongoing and may help to clarify the role of the FGFR in MPM. [NCT01769547].

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    MINI 29 - Meta Analyses and Trial Conduct (ID 156)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      MINI29.06 - Are Clinical Trial Eligibility Criteria an Accurate Reflection of a Real World Population of Advanced Lung Cancer Patients? (ID 1398)

      19:00 - 19:05  |  Author(s): S.A. Laurie

      • Abstract
      • Presentation
      • Slides

      Background:
      Modern systemic treatment options for advanced NSCLC have largely been established from clinical trials (CTs). It is estimated that less than 10% of cancer patients enter a CT, but this subgroup drives oncology practice and impacts treatment decisions for other cancer patients. The advantage of CTs comes from solid internal validity and stringent methodology. Nonetheless, the generalizability of CTs could be questioned due to the high selectivity of eligibility criteria. We investigated clinical trial eligibility in an unselected NSCLC population

      Methods:
      With ethics approval, a retrospective chart review was performed of patients with de novo advanced NSCLC assessed by medical oncologists at a large academic cancer centre, serving a mixed urban and rural population, between September 2009 and September 2012. Data collected included patient demographics, stage, performance status, histology, treatment details and outcome. Two sets (A and B) of arbitrary eligibility criteria were created using common criteria from phase 3 CTs. These criteria were applied to this cohort to identify the proportions of patient who would hypothetically qualify for CT enrollment. Criteria A required: ECOG 0 or 1, absence of brain metastases, Creatinine < 120 and the absence of second malignancy. Criteria B, allowing broader inclusion, only required ECOG 0-2 and Creatinine < 120. We investigated survival among eligible/ineligible and treated/untreated patients.

      Results:
      528 patients were included: 55% male; 50% ECOG 0-1; 58% adenocarcinoma, 22% squamous cell; 7% stage IIIB and 93% stage IV. Using the strict CT criteria (A), only 144 (27%) patients were considered eligible. Of those, 79% actually received systemic therapy. From 384 patients who would have been ineligible for the CT, 178 patients (46%) still received systemic therapy. There was a trend to longer median overall survival (mOS) in the eligible treated compared to eligible non-treated patients (11.6 vs 8.1 months p=0.12). mOS was significantly longer in the non-treated eligible cohort compared to the non-treated ineligible cohort (8.1 vs 3.8 months p=0.003). The eligible treated and non-eligible treated had similar mOS ( 11.6 vs 10.2 months, p= 0.10). When less strict eligibility criteria (B) were applied, 343 patients (65%) would have been eligible, of whom 240 patients (70%) actually received systemic therapy. From the remaining ineligible 185 patients, only 51 (28%) received treatment. The mOS was similar in the treated patient whether eligible or ineligible (10.9 vs 10.1 months, p=0.57). As seen in criteria A, significantly longer mOS was observed in the eligible untreated compared to the ineligible untreated ( 4.9 vs 3.5 months p<0.001).

      Conclusion:
      While clinical trial criteria restrict study entry to the fittest patients, these results suggest that they do not reflect the broader patient population, as many ‘ineligible’ patients received therapy. Extrapolation of treatment paradigms to non-trial eligible populations is common, and may be reasonable based on these results. We observed similar survival among treated patients, whether trial eligible or not. This suggests that clinical judgement is more important than trial eligibility. In order to broaden trial participation, we could hypothesize that trial eligibility criteria could be relaxed.

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    P1.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 206)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P1.01-034 - Is There A "Physician Effect" in Medical Oncology? (ID 1408)

      09:30 - 09:30  |  Author(s): S.A. Laurie

      • Abstract
      • Slides

      Background:
      Non-small cell lung cancer (NSCLC) is the commonest cause of cancer death globally, with a 5-year survival of 16%. Known prognostic factors include stage, performance status (PS) and gender, but does the choice of physician affect patient outcome? We assessed practice variations of four medical oncologists treating advanced NSCLC, investigating this impact on overall survival (OS).

      Methods:
      Following ethics approval, a retrospective analysis was undertaken of all newly diagnosed stage 4 NSCLC patients seen in out-patient consultation at our institution between 2009 and 2012. All physicians accepted unselected lung cancer referrals and all patients are included. Baseline demographics, systemic therapy received, reasons for not receiving therapy, and OS data were collected. Cox regression analyses (univariate and multivariate) were employed to assess determinants of OS. The physicians were blinded to the results.

      Results:
      Overall 528 patients were included. Baseline characteristics are shown in table 1. A significant variation was noted in the proportion receiving any systemic chemotherapy (p≤0.01) [D(60%), L(65%), R(43%), M(52%)] (Figure 1A). However OS was not statistically significantly different among all patients (p=0.47), among treated patients (p=0.18) or among untreated patients (p=0.22)(Table and Figure 1B). In multivariate analysis, factors associated with survival were PS (p<0.01), weight loss (<5%, ≥5%)(p<0.01), WBC (<11, ≥11)(p=0.0588) and platelets (<400, ≥400)(p=0.0374).Figure 1

      Demographic Overall (n=528) Physician R (n=137) Physician M (n=118) Physician D (n=115) Physician L (n=158) p-value
      Median Age 68 70 68 67 67 0.23
      Gender (male) 55% 58% 58% 49% 56% 0.42
      PS (0-1) 50% 47% 48% 50% 55% 0.01
      Hg (<100) 6% 11% 3% 4% 4% 0.01
      LDH (<250) 28% 21% 30% 27% 33% 0.09
      Platelets (<400) 71% 64% 75% 78% 70% 0.12
      Weight loss (>5%) 48% 49% 48% 46% 49% 0.87
      WBC (<11) 62% 56% 68% 68% 60% 0.11
      Received ≥ 1 line systemic therapy 55% 43% 52% 60% 65% <0.01




      Conclusion:
      While practice size and proportion of patient treated did vary between oncologists, these did not translate into significantly different survival. There were statistically significant differences in the distribution of baseline characteristics between the 4 oncologists and this could cause the differences in proportion of patients treated. We hypothesize that as long as the oncologists are well trained and display good practice, survival is not dependant on the individual. This research does not measure other valuable characteristics or outcomes such as rapport, compassion, and quality of life, which may differ between physicians.

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    PC 02 - Pro vs Con: Is There a Role for EGFR TKIs in EGFR Mutation Negative Disease? / Pro vs Con: Whole Exome Sequencing vs. Selected Testing (e.g., ALK and EGFR) (ID 48)

    • Event: WCLC 2015
    • Type: Pro Con
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      PC02.01 - Is There a Role for EGFR TKIs in EGFR Mutation Negative Disease? - Pro (ID 2030)

      14:20 - 14:40  |  Author(s): S.A. Laurie

      • Abstract
      • Presentation

      Abstract:
      With the dramatic clinical benefit that can be observed using tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) in patients with non-small cell lung cancer (NSCLC) harbouring activating mutations in EGFR, there has understandably been a focus on the use of these agents in this subset of NSCLC. However, EGFR mutation positive NSCLC represents only approximately 10 – 15 % of all non-squamous NSCLC in non-East Asian patients, and a substantial proportion of East Asian patients do not harbour this mutation. Thus, world-wide, the vast majority of those with NSCLC are so-called “wild-type” for EGFR. For these patients, it is clear from randomized clinical trials that the treatment of choice in the first-line metastatic setting is platinum-doublet chemotherapy. Increasing data suggest that chemotherapy may be preferred in the second-line setting. Is there any role for the use of EGFR TKIs in the wild-type population? Randomized data in which an EGFR TKI is compared to placebo in both the maintenance and refractory settings suggest that there may be. NCIC Clinical Trials Group study BR21 [1] which randomized 731 unselected patients to either erlotinib or matching placebo, was designed and conducted prior to the discovery of activating mutations. Patients had received 1 (50 %) or > 2 (50 %) lines of prior therapy; > 90 % had received a platinum-doublet. An improvement in median survival (6.7 versus 4.7 months [HR 0.70, p < 0.001]) was also associated with a quality of life benefit. This benefit was consistent across subgroups, including in the 50 % of patients with non-adenocarcinoma histology. In a separate analysis of ever-smokers with squamous histology, patients highly unlikely to harbour an EGFR mutation, the magnitude of survival benefit was the same as in the overall study population (median 5.6 versus 3.5 months [HR 0.66, p=0.009])[2]. The SATURN trial [3] randomized 889 patients who had not progressed after 4 cycles of platinum-doublet chemotherapy to either erlotinib or placebo. While of debatable clinical relevance, there was a statistically significant one month prolongation of median survival with the use of erlotinib (HR 0.81, p=0.009). A similar effect was observed in the 44 % of patients with known EGFR wild-type status (HR 0.77, p=0.02). In a pre-planned subgroup analysis [4], a greater magnitude of benefit was observed in those patients whose best response to induction chemotherapy was stable disease (median overall survival 11.9 versus 9.6 months [HR 0.72, p=0.002]), with a similar effect noted in those patients with squamous histology (HR 0.67, p=0.01), and those known to be EGFR wild-type (HR 0.65, p=0.004). Maintenance erlotinib has been shown to not negatively impact quality of life [5], and when used in those with stable disease, to be cost effective [6]. Meta-analyses of placebo-controlled trials of EGFR TKIs in the maintenance setting have confirmed a modest progression-free survival benefit in squamous [7] and known wild-type [8] patients. Multiple trials have compared an EGFR TKI to either docetaxel or pemetrexed in the second-line setting. The TAILOR trial [9], the only trial to prospectively determine and enrol only wild-type patients, showed a clear PFS advantage to docetaxel, and a trend towards improved overall survival. However several other trials that enrolled patients who were unselected with regard to EGFR status had a substantial number of wild type patients, and none of these trials demonstrated a difference in overall survival in wild-type patients between an EGFR TKI and chemotherapy. While these were retrospective analyses on only a subset of enrolled patients with available tissue, wild-type patient numbers in many trials approached (and in one exceeded) the number of patients enrolled to TAILOR. Further, unlike other trials, TAILOR prohibited crossover, which may have impacted survival results, particularly for patients with squamous carcinoma in the erlotinib arm. Taken together these trials suggest that a treatment strategy that includes both chemotherapy and an EGFR TKI sequentially, irrespective of order, will lead to a similar length of survival provided patients receive both lines of therapy. In platinum-pretreated patients who are fit it is likely preferred to use chemotherapy and then at progression move on to an EGFR TKI, as the chance of patients receiving both treatments is higher. Additional data to suggest that EGFR TKIs may have activity in wild-type patients comes from several small, randomized phase II trials comparing second-line chemotherapy with the same chemotherapy with intercalated EGFR TKIs. These studies have shown prolonged PFS in patients treated with the combination. What these trials demonstrate is that EGFR TKIs appear to have a modest treatment effect in EGFR wild-type patients. In these days of targeted therapies leading to substantial treatment effects in a variety of tumours with oncogenic drivers, is this magnitude of benefit sufficient? In lung cancer, many other treatments have been adopted for a similar magnitude of benefit. Although objective response rates to EGFR TKIs are low in wild-type patients, they are also low to standard cytotoxic chemotherapies beyond first-line, and it seems possible that there is a larger proportion of patients with stabilization of disease and / or slowing of progression that is clinically relevant. Not all oncologists or patients will feel that a trial is warranted, but an EGFR TKI is a reasonable choice as last-line therapy when the option is no further treatment, or as maintenance treatment in patients with squamous histology following a best response of stable disease to induction platinum-based chemotherapy. EGFR “wild-type” is a heterogeneous, not homogeneous, population, and as with any therapy, only a subgroup of patients will benefit from treatment. However a consistent reproducible biomarker for benefit in the wild-type subgroup has not yet been discovered. EGFR protein expression, gene copy number, Kras status and serum proteomics have all been evaluated with at times conflicting results, due to limited samples and the retrospective nature of the analyses. The development of rash may be a pharmacodynamic predictor of greater efficacy [10]. Additional work is required to determine which wild-type patients may derive benefit from an EGFR TKI, to avoid needless toxicity and improve cost-effectiveness. References 1. Shepherd et al. N Engl J Med 353: 123-132, 2005 2. Clark et al. Clin Lung Cancer 7:389-394, 2006 3. Cappuzzo et al. Lancet Oncol 11:521-529, 2010 4. Coudert et al. Ann Oncol 23:388-394, 2012 5. Juhasz et al. Eur J Cancer 49:1205-1215, 2013 6. Walleser et al. Clinicoeconomics Outcomes Res 4:269-275, 2012 7. Ameratunga et al. Asia-Pacific J Clin Oncol. 10:273-278, 2014 8. Vale et al. Clin Lung Cancer 16:173-182, 2015 9. Garassino et al. Lancet Oncol 14:981-988, 2013 10. Ding et al. Contemp Clin Trials 29:527-536, 2008

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