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W. Lim



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    MO10 - Molecular Pathology II (ID 127)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      MO10.06 - Intertumour heterogeneity revealed by integrative analysis of targeted somatic mutation profiling and whole genome copy-number alterations in non-squamous non-small cell lung carcinomas (ID 3386)

      16:45 - 16:50  |  Author(s): W. Lim

      • Abstract
      • Presentation
      • Slides

      Background
      Molecular subtypes of NSCLC are delineated through single driver alterations, although this likely underestimates the extent of inter-tumor heterogeneity. The goal of this study was to evaluate the potential impact of co-occuring mutations and copy number alterations in a series of tumours from both East-Asian (EA) and Western-Europe (WE) origins.

      Methods
      230 non-squamous non-small cell lung carcinomas (NSCLC) were analysed using the MassARRAY LungCarta™ panel (Sequenom) which examines 214 mutations in 26 oncogenes and tumour suppressor genes. Results were integrated with copy number alterations evaluated using Affymetrix Genome-Wide Human SNP 6.0 arrays and clinical variables.

      Results
      Out of the 230 tumours tested, 185 mutations were observed, with 138 tumours (60%) with at least one mutation – 97 tumours (42.2%) with a single mutation in a single gene, 36 tumours (15.7%) with two mutations (either in the same gene or two different genes), four tumours (2.2%) with three mutations and one with four mutations. The most frequent mutations were EGFR (38.5% EA;10.1% WE), KRAS (10.9% EA;31.6% WE), P53 (8.8% EA;15.1% WE), MET (14.3% EA;2.2% WE), STK11 (9.9% EA;2.8% WE) and PIK3CA (2.2% EA;4.3% WE). Co-occurring mutations were found in up to 30% of tumors, although the likelihood differed for each gene: KRAS (16/54, 31%), EGFR (18/49, 37%), MET (6/16, 38%), P53 (13/29, 45%), STK11 (8/13, 62%) and PIK3CA (5/8; 62%). Among the eight tumors harbouring PIK3CA mutations, five cases had a co-mutation (four cases with EGFR, one case with KRAS). In EGFR mutant cancers, co-occuring mutations include p53 (10%), PIK3CA (8%), STK11 (6%) and MET (4%). Significant relationships were also detected between EGFR mutation and CNAs on chromosomes 1p, 7p, and 13q. There were also significant relationships between KRAS mutation and CNAs on chromosomes 1q and 3q. For stage I, we found a worse prognosis for patients with at least one mutation. PIK3CA was significantly correlated with poor prognosis. Consistent with recent pooled analysis, KRAS alone is not prognostic but when CNAs and mutation status are combined, patients having both KRAS mutation and the highest related CNA (3q22.3 copy loss) showed a significant poorer prognosis.

      Conclusion
      This study highlights the wide diversity of mutation profiles within molecularly-defined NSCLCs, revealing co-mutations and associations with numerical chromosomal abnormalities that are clinically relevant. This diversity should be taken into account when designing stratified treatment approaches and underscores the need for customized assays that broadly screen for “actionable” mutations and copy-number alterations.

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    O03 - NSCLC - Targeted Therapies I (ID 113)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O03.03 - Outcomes of NSCLC patients on Phase I Trials: The Importance of Molecular and Patient Selection (ID 3349)

      10:50 - 11:00  |  Author(s): W. Lim

      • Abstract
      • Presentation
      • Slides

      Background
      With recent successes of targeted therapeutics, there has been increased enthusiasm to enroll patients with NSCLC into phase I trials. Most phase I prognostic indices have been derived from patient populations where NSCLC is underrepresented.

      Methods
      Retrospective review of NSCLC patients enrolled between 2005-2012 at National Cancer Centre Singapore was performed, collating data on demographics, molecular profiles, trial characteristics and clinical outcomes (using RECIST criteria) to identify prognostic factors to improve patient selection.

      Results
      167 patients were treated on 20 phase I trials. Median (range) age 60.7 years (22.7–84.7), 58% male, adenocarcinoma/squamous/NOS/others (75.4%/9.6%/12.6%/2.4%). 13% were at high risk of nutritional deficiency (BMI<18.5), and ECOG 0(21%)/1(77%)/2(2.4%). Median (range) prior chemotherapy was 2 (0-6) and 99% received at least one treatment line. Class of agents include anti-angiogenics (50.3%), signal transduction pathway inhibitors (STPi) 46%. Only 4.2% received cytotoxics alone. 86.2% were on combination regimens, of which two-thirds on combinations of chemotherapy and small molecule. Between 2008-2012, proportion of patient tumors with molecular alterations identified increased from 5.5% to 62.5%, facilitating enrolment into trials designed for a specific genotype (or “matched” trials). 35% and 7.8% of patients participated on trials targeting EGFR and ALK alterations respectively. With a median follow up of 8.7 months, progression free survival was 3.9m (95%CI:3.4–5.8), overall survival (OS) 10.4m (95%CI:8.0–11.7). Among evaluable patients, 24.8% (95%CI:18.2–32.5) had complete/partial response; clinical benefit rate (CBR) 75.8% (95%CI:68.2–82.4). 90-day mortality (90DM) was 15%. Patients participating in “matched” trials had a lower risk of death (HR 0.55 [95%CI:0.38-0.78] p<0.001) compared to those on unselected or “unmatched” trials (median OS 11.9 v 7.6). On univariate analysis, low BMI<18.5, ECOG>0, ≥3 metastatic sites, presence of bone metastasis, low albumin (<35), low Hb (<12), ≥ 3 prior lines of chemotherapy and non-participation in a "matched" trial were significant negative prognostic factors for OS. On multivariate analysis, ECOG, number of metastatic sites, albumin and trial type (targeting EGFR/ALK/others), emerged as independent variables. These factors were used to construct a prognostic nomogram to predict OS at 3, 6 and 12m. Of 12 published prognostic indices, 8 models were validated in our patient cohort, with the highest c-index being 0.66. Pairwise comparison against these 8 (7 tumor agnostic; 1 NSCLC) prognostic indices, found the nomogram to be superior in predicting OS, with a c-index of 0.74.

      Conclusion
      This is the largest analysis of phase I NSCLC patients using individual patient data. Outcome of NSCLC patients in phase I trials is promising with CBR 76% and median OS 10.8m. Our nomogram – comprising of ECOG, albumin, number of metastatic sites, participation in a “matched” trial – is uniquely derived from NSCLC patients and was a better predictor of OS compared to 8 published phase I prognostic scores.

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    P1.10 - Poster Session 1 - Chemotherapy (ID 204)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.10-040 - Lung cancer outcomes in an era of more options - Survival analysis from an Asian cancer center (ID 2193)

      09:30 - 09:30  |  Author(s): W. Lim

      • Abstract

      Background
      Lung cancer therapy has changed in the last decade with the advent of EGFR tyrosine kinase inhibitors (TKI) and newer chemotherapeutics such as pemetrexed. Most of these benefits have been limited to lung adenocarcinoma and not other histological subtypes. In addition, this has translated to improved progression free survival benefits but no apparent overall survival benefits in some of the phase III studies conducted. We hypothesized that the benefits seen in these phase III clinical trials would translate to improved overall survival in the wider population of patients (pts) treated in a cancer center.

      Methods
      We conducted a survival analysis of all primary stage 3B/4 lung cancer diagnoses available from a cancer center database between 1 Jan 2000 and 31 Dec 2012. The diagnoses were identified based on ICD-9 162 and ICD-10 C34. Recurrent lung cancers were excluded. Histological classification for analysis was based on the IASLC system. Molecular data from adenocarcinoma (AC) was available with routine testing from 2010. Treatment given in the form of pemetrexed and EGFR TKI was also tracked from the pharmacy system from 2001. Vital status was checked against the National Registry of Births and Deaths as at 31 March 2013. The primary endpoint was overall survival (OS) which was defined from the time of diagnosis till death from any cause or last follow-up and estimated using Kaplan-Meier method. Log-rank test was used to compare survivals. Jointpoint regression models were used for trend analyses.

      Results
      A total of 5320 cases of stage 3B/4 primary lung cancer diagnoses were identified. The cases were predominantly male (65%) and Chinese (81%). The median age at diagnosis and gender distribution among the diagnoses in each year remained stable over time. Non-small cell lung cancer (NSCLC) made up 92% of all diagnoses. NSCLC subtypes were adenocarcinoma (52%), squamous (13%), large cell (2%), and Others (25%). EGFR mutation rate among 708 tested cases was 55%, and ALK translocation rate among 108 tested cases was 9%. The jointpoint regression model identified 2005 as a significant turning point in improvement in median OS. Hence comparing 2001-2005 and 2006-2010, the median OS for the entire cohort improved from 8.0 mths (95% CI, 7.1-8.7) to 9.5 mths (95% CI, 8.9–10.2), p = 0.001. This median OS survival benefit was contributed by OS benefits in AC 10.3 mths (95% CI, 9.3-11.8) vs 13.3 mths (95% CI, 12.1 -14.5). The turning point for improvement for median OS survival coincided with increased usage of EGFR TKI and pemetrexed from 2006 and 2008 respectively.

      Conclusion
      There is median OS benefit in lung cancer treatment outcomes tracked over a decade. This observed benefit is in tandem with the increased use of drugs that have clinical benefit in adenocarcinoma. Unmet needs remain for both small cell lung cancer and other NSCLC subtypes.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-030 - Transaminitis induced by epidermal growth factor receptor tyrosine kinase inhibitor predicts for favourable outcome in EGFR mutation positive non-small cell lung cancer (ID 2203)

      09:30 - 09:30  |  Author(s): W. Lim

      • Abstract

      Background
      Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are used as first-line therapy in patients with advanced non-small cell lung cancer (NSCLC) harbouring sensitizing mutations. Transaminitis is a known complication, and may impede the delivery of optimal doses of TKIs. We describe the incidence and severity of TKI induced transaminitis in patients with NSCLC treated with first line EGFR TKI and investigate its association with clinical outcomes. In addition, we review the management of patients who developed Grade 2/3 (G2/3) transaminitis or other TKI toxicity.

      Methods
      A retrospective study of 127 patients with EGFR mutation positive NSCLC treated at the National Cancer Centre Singapore with TKIs (gefitinib or erlotinib) over seven years (1/1/2006-30/5/2012) was conducted. Transaminitis was graded in accordance with CTCAE v4.0 criteria. Endpoints included dose adjustments, progression free survival (PFS) and overall survival (OS).

      Results
      Of 127 patients, 85 (66.9%) developed at least CTCAE v4.0 all grade transaminitis (G1/2/3: 75.3/11.8/12.9%) and 39 (30.7%) developed G1/2 bilirubin levels. No patients developed Grade 4 transaminitis. None had encephalopathy suggestive of fulminant liver failure. Median duration to onset of transaminitis was 1.87 months. Of 24 patients who had G2/3 transaminitis (n=21) or stopped TKI therapy due to other TKI toxicity (n=3), 8 switched to alternative regimen and/or therapies (alternative TKI only, n=3; alternative dosing schedule only, n=2; alternative dosing schedule followed by alternative TKI, n=2; switch to chemotherapy followed by alternative TKI, n=1). There was no change in TKI treatment and/or regimen for the other 16 patients. Development of transaminitis was independent of age, gender, smoking status and presence of brain metastases at baseline. Patients who developed transaminitis (all grades) had significantly longer PFS than those who did not (12.4 vs 8.2 months) (p=0.002). Patients with G1 ALT/AST had significantly longer PFS compared to G2/3 (G1/G2/G3: 13.4/3.0/11.9 months) (p=0.034). OS was not significantly affected by the presence and severity of transaminitis.

      Conclusion
      The incidence of EGFR TKI induced transaminitis in this cohort of patients appears higher than previously reported. Transaminitis, in particular G1, may be predictive of PFS for patients on TKIs. Patients should be monitored for the development of transaminitis, especially during the first two months of TKI treatment. Further studies are recommended to evaluate the role of transaminitis as a marker for TKI treatment efficacy.