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N.B. Leighl



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    MO08 - NSCLC - Early Stage (ID 117)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO08.08 - A cost-effectiveness analysis of the 15-gene expression signature in guiding adjuvant chemotherapy in early stage non-small cell lung cancer based on the JBR.10 trial (ID 1962)

      17:00 - 17:05  |  Author(s): N.B. Leighl

      • Abstract
      • Presentation
      • Slides

      Background
      The NCIC CTG JBR.10 trial demonstrated that adjuvant chemotherapy (ACT) improves survival in resected stage IB/II non-small cell lung cancer (NSCLC) compared to observation. A 15-gene expression signature was developed from the trial population and subsequently validated to stratify patients with resected NSCLC into low and high risk prognostic groups. The signature may also be predictive for greater benefit from ACT in high risk patients (Zhu et al. JCO 2010), but this has not yet been validated. This gene expression signature may offer a risk stratification strategy to identify patients most likely to benefit from ACT. We conducted an exploratory economic analysis to assess the impact of the use of this gene signature compared to current clinical staging to guide ACT decisions in resected early stage NSCLC.

      Methods
      We developed a decision analytic model populated by the NCIC CTG JBR.10 trial cost and outcome data, including direct medical costs and overall survival (OS). Utility for each health state was estimated from quality of life data to generate quality-adjusted survival. The analysis was performed over a lifetime horizon from the perspective of the Canadian public health care system, expressed in 2013 Canadian dollars. Survival and costs were discounted at 5% per year. We determined the incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratio (ICUR) of ACT versus observation in resected stage IB/II NSCLC in the following two scenarios: (1) gene signature-directed ACT, where patients classified as having high risk of recurrence receive ACT and those at low risk are observed; and (2) clinical stage-directed ACT, where gene signature profiling is not performed – those with stage IB tumours >4cm or stage II NSCLC receive ACT, and those with stage IB tumours <4cm are observed. Nonparametric bootstrapping to estimate 95% confidence intervals (CI) and multi-way sensitivity analyses were performed.

      Results
      The analysis included 52 patients in the gene signature-based strategy and 125 patients in the stage-based strategy with available direct medical costs and gene signature data. The mean survival gain of ACT versus observation was 2.28 years using gene signature-directed selection, and 1.59 years using stage-directed selection. The discounted ICER of ACT versus observation was $8,327/life-year gained (LYG; 95% CI, $395 to $19,590) using the gene signature-directed approach, and $5,623/LYG (95% CI, -$2,161 to $14,354) for the clinical approach. There was no significant difference in the ICER between the two strategies (p=0.52). The discounted ICUR was $11,315/quality-adjusted life-year (QALY; 95% CI, $211 to $27,314) using the gene signature-directed approach, and $7,728/QALY (95% CI, -$3,080 to $19,825) for the clinical approach. Sensitivity analyses showed that the ICER was most sensitive to changes in the survival hazard ratio (i.e. treatment benefit) and utility, but less sensitive to the cost of the gene signature (range $0 to $10,000 per case, with corresponding ICER $15,794 to $28,194/LYG, respectively).

      Conclusion
      This exploratory analysis suggests that use of the 15-gene expression signature to guide decisions for ACT in resected stage IB/II NSCLC patients could be highly cost-effective. Further validation of the signature’s impact on ACT outcomes is needed.

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    MO18 - NSCLC - Targeted Therapies IV (ID 116)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 2
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      MO18.10 - Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with pemetrexed in a phase 1/1B trial involving <em>KRAS</em>-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): efficacy and biomarker results (ID 2922)

      17:10 - 17:15  |  Author(s): N.B. Leighl

      • Abstract
      • Presentation
      • Slides

      Background
      KRAS is the most frequently mutated oncogene in NSCLC and represents an unmet need for targeted therapy. Trametinib plus pemetrexed enhances growth inhibition and apoptosis of NSCLC cell lines with and without RAS/RAF mutations in vitro when compared with either agent alone.

      Methods
      This 2-part, multi-arm, open-label phase 1/1B study evaluated the safety and efficacy of trametinib plus chemotherapy (NCT01192165). Part 1 determined the recommended phase 2 dose (RP2D) for trametinib (1.5 mg daily) and pemetrexed (500 mg/m[2] every 3 weeks) in patients with advanced solid tumors. In part 2, patients with NSCLC were stratified as KRAS WT or KRAS-mutant and treated at the RP2D. Primary study objectives were safety and tolerability; secondary objectives were efficacy and pharmacokinetics (PK). Next-generation sequencing was used to perform exploratory mutational profiling on available archival tissue from 21 patients (50%). Plasma from 38 patients (90%) was analyzed both for tumor-derived mutations in cell-free DNA (eg, KRAS, EGFR) using BEAMing technology as well as cytokine and angiogenic factors using a Searchlight multiplex assay.

      Results
      A total of 42 patients with NSCLC (19 KRAS WT [79% ≥ 2 prior therapies; 74% prior pemetrexed; 16% squamous] and 23 KRAS-mutant [57% ≥ 2 prior therapies; 43% prior pemetrexed; 4% squamous]) were enrolled and treated at the RP2D until disease progression or unacceptable toxicity. Safety and PK data were previously reported (ASCO 2013). Response rate was 17% and disease control rate was 69% for the whole population of NSCLC. Of note, we observed disease control in 75% of patients previously treated with pemetrexed (including 4 partial responses [PRs]) and in 2 patients out of 4 with squamous histology (including one PR). Progression-free survival (PFS) was 5.1 months for all patients with NSCLC. Detailed efficacy results according to mutation status are shown in Table 1. Among KRAS WT, activity was seen in cancers with EGFR mutations or ALK rearrangement. Final biomarker analyses, including assessment of their potential correlation with therapeutic response or resistance, are ongoing and will be reported upon completion. Figure 1

      Conclusion
      MEK inhibition with trametinib + pemetrexed demonstrated activity in both KRAS-mutant and WT NSCLC; efficacy data are encouraging and warrant further study. There was no significant difference in activity or efficacy across KRAS mutation subtypes. Interestingly, activity with this combination was broad and was seen in patients with squamous histology, patients with prior pemetrexed treatment, and those with EGFR mutation or ALK translocation.

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      MO18.11 - Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with docetaxel in a phase 1/1B trial involving <em>KRAS</em>-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): efficacy and biomarker results (ID 2411)

      17:15 - 17:20  |  Author(s): N.B. Leighl

      • Abstract
      • Presentation
      • Slides

      Background
      KRAS is the most frequently mutated oncogene in NSCLC and represents an unmet need for targeted therapy. Trametinib enhances docetaxel-induced growth inhibition and apoptosis of NSCLC cell lines. Cell lines with the KRAS G12C point mutation, the most common KRAS mutation subtype (≈50% of KRAS-mutant NSCLC or ≈10% of all NSCLC), are more responsive to apoptosis induced by this combination.

      Methods
      This 2-part, multi-arm, open-label phase 1/1B study evaluated the safety and efficacy of trametinib plus chemotherapy (NCT01192165). Part 1 determined the recommended phase 2 dose (RP2D) for trametinib (2.0 mg daily) and docetaxel (75 mg/m[2] every 3 weeks) in the presence of growth factors in patients with advanced solid tumors. In part 2, patients with NSCLC were stratified as KRAS WT or KRAS-mutant and treated at the RP2D. Primary study objectives were safety and tolerability; secondary objectives were efficacy and pharmacokinetics (PK). Next-generation sequencing was used to perform exploratory mutational profiling on available archival tissue from 17 patients (36%). Plasma from 42 patients (89%) was analyzed both for tumor-derived mutations in cell-free DNA (eg, KRAS, EGFR) using BEAMing technology as well as cytokine and angiogenic factors using a Searchlight multiplex assay.

      Results
      A total of 47 patients with NSCLC (22 KRAS WT [64% ≥2 prior therapies; 27% squamous] and 25 KRAS-mutant [40% ≥2 prior therapies; 0% squamous]) were enrolled and treated at the RP2D until disease progression or unacceptable toxicity. Safety and PK data were previously reported (ASCO 2013). Progression-free survival (PFS) was 4.2 months for all patients; efficacy results according to mutation status are shown in Table 1. Among KRAS-mutant patients, activity and efficacy were better in G12C compared with non-G12C subtypes. Among KRAS WT, activity was seen in cancers with EGFR mutations; clinical benefit was noted in 2 patients with ALK translocation (disease control 25 weeks and 60+ weeks). Final biomarker analyses, including assessment of their potential correlation with therapeutic response or resistance, are ongoing and will be reported upon completion. Figure 1

      Conclusion
      MEK inhibition with trametinib + docetaxel (+ growth factors) demonstrated activity in both KRAS-mutant and WT NSCLC; efficacy data are encouraging and warrant further study. Cancers carrying the KRAS G12C point mutation may have improved activity and efficacy compared with non-G12C subtypes, consistent with preclinical observations. Additionally, clinical benefit with this combination was broad and was seen in patients with squamous histology and those with EGFR mutation or ALK translocation.

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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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      P1.11-020 - Economic Analysis of TORCH: Erlotinib versus Cisplatin and Gemcitabine as First-Line Therapy for Advanced Non-Small Cell Lung Cancer (NSCLC) (ID 1645)

      09:30 - 09:30  |  Author(s): N.B. Leighl

      • Abstract

      Background
      The TORCH (“Tarceva or Chemotherapy”) randomized phase III trial demonstrated that first-line erlotinib followed by second-line cisplatin-gemcitabine (N=380) compared to cisplatin/gemcitabine followed by erlotinib (N=380) in unselected advanced NSCLC patients yielded inferior survival, without major differences in first-line global quality of life. We determined the incremental costs and utility between arms, including in the EGFR mutation positive subgroup (N=39).

      Methods
      Direct medical resource utilization data and EQ5D scores were collected prospectively during the trial. Mean survival and quality-adjusted survival per arm were calculated for the entire study population and the subgroup with documented EGFR mutations. The analysis was conducted from the Canadian public health perspective, using a lifetime horizon. Costs for medications, outpatient visits, investigations and toxicity management including hospitalization were determined, and presented in 2012 Canadian dollars (CAD). The primary outcomes of the analysis included costs and outcomes per treatment arm, and the incremental cost per quality-adjusted life-year (QALY) gained in the EGFR mutation positive subgroup.

      Results
      The costs per patient in the chemotherapy were higher than in the erlotinib arm, with an incremental mean cost of $4,190 CAD. This was related to longer duration of chemotherapy treatment, associated with higher drug and outpatient visit costs. Higher costs from hospitalization and adverse event management were seen in the erlotinib arm, likely related to disease progression. Mean overall survival in the entire study population was longer in the chemotherapy arm , although mean quality-adjusted survival was similar (0.82 QALY in chemotherapy arm and 0.87 in erlotinib arm). In the EGFR mutation positive subgroup, mean survival was slightly higher in the chemotherapy arm, but quality-adjusted survival was longer in the erlotinib arm (1.19 QALYs versus 1.08 QALYs with chemotherapy). The incremental cost-effectiveness ratio for first-line erlotinib compared to chemotherapy in the EGFR mutation positive subgroup was $32,916 CAD per QALY.

      Conclusion
      While first-line platinum doublet chemotherapy remains the standard for unselected advanced NSCLC patients, first-line erlotinib appears to be cost effective in the EGFR mutation positive subgroup. This supports routine EGFR genotyping to select first-line therapy in advanced NSCLC, and targeted EGFR TKI therapy for those with EGFR mutation positive NSCLC.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-044 - Clinical impact of EGFR mutation fraction and tumour cellularity in EGFR mutation positive NSCLC (ID 2982)

      09:30 - 09:30  |  Author(s): N.B. Leighl

      • Abstract

      Background
      We investigated the impact of mutation fraction, tumour sample cellularity, and diagnostic specimen type on EGFR TKI response, time to treatment failure (TTF) and overall survival (OS), as well as patterns of treatment in a population-based cohort of advanced EGFR mutation positive NSCLC patients.

      Methods
      From March 2010 to May 2012, EGFR testing in the province of Ontario (Canada) was conducted at a single centre, using fragment analysis for exon 19 deletion and Sau961 restriction enzyme digest for exon 21 mutations. Patients with EGFR mutation positive samples were identified and tumour sample cellularity, mutation fraction (percent of tumour cells mutated), demographic, treatment and outcome data were collected. Regression analysis was undertaken to assess the association between demographic variables, mutation fraction, tumour sample cellularity and sample type on clinical outcomes.

      Results
      Among 293 patients identified with EGFR mutation positive NSCLC, 253 received EGFR TKIs and are included in this analysis. Most are female (72%), never smokers (59%), have exon 19 deletions (53%; 47% exon21 L858R), and median age 65 years (range 26 to 96). Tumour specimens tested include resection (32%), cytology (30%), and core biopsies (38%). Median EGFR mutation fraction is 30% (range 0.4% to 96%); 24% had a low (≤10%) mutation fraction, and 13% had a mutation fraction ≤5%. Responses (any tumour reduction) were seen in 62%, mixed response or stable disease in 25%, and progression as the best response in 13%. Median TTF from the start of EGFR TKI therapy is 13.2 months (range 0-43.7 months). Median OS from TKI start is 22.3 months (95% CI: 19.5-28.2 months), with 1-, 2- and 3-year survival rates of 72%, 49% and 37%. In multivariable analysis, factors associated with TTF included female sex (HR 0.69, p=0.03) and sample type (resection HR 0.56, cytology HR 0.82, core biopsy as reference, p=0.01). Age at metastatic diagnosis (p=0.01), sample cellularity (p=0.01) and sample type were significantly associated with OS, (resection HR 0.51, cytology HR 0.70, core biopsy as reference, p=0.04). Proportional odds logistic regression identified that mutation frequency and age at metastatic diagnosis were significantly associated with the odds of response, (p=0.047, p=0.04 respectively). Responses were seen even in those with lower EGFR mutation fraction, 48% (24/50) at a mutation frequency of ≤10% and 33% (9/27) at a mutation frequency of ≤5%. The average cellularity in the high (>10%) mutation fraction group was 53% (95%CI 50– 56%), and 36% (95%CI 29 – 43%) in those with a low mutation fraction (p<.0001).

      Conclusion
      Pathologic features may be relevant to clinical outcomes in EGFR mutation positive NSCLC, including mutation fraction, sample cellularity, and specimen tested. The clinical relevance of sample tumour cellularity and sample type tested remains unclear. In particular, initial stage and prognosis may be confounders in the association between resected specimens and favourable outcomes. Given that those with mutation fractions ≤5% may have significant response from EGFR TKI therapy, treatment should not be withheld on the basis of mutation frequency alone.