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M.F. Renschler



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    MO24 - NSCLC - Chemotherapy III (ID 110)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO24.07 - nab-Paclitaxel plus carboplatin in patients (pts) with squamous cell (SCC) non-small cell lung cancer (NSCLC): analysis of pts treated beyond 4 cycles in a pivotal phase 3 trial (ID 3438)

      10:30 - 12:00  |  Author(s): M.F. Renschler

      • Abstract
      • Presentation
      • Slides

      Background
      Continuous maintenance is defined as continuation of ≥ 1 first-line agents after 4-6 cycles of induction therapy in pts who have not progressed. In a pivotal phase 3 trial, first-line treatment to progression with nab-paclitaxel (nab-P, 130-nm albumin-bound paclitaxel particles) + carboplatin (C) vs solvent-based paclitaxel (sb-P) + C resulted in a 68% improvement in response rate (41% vs 24%; P < .001) and a trend toward improved survival (median, 10.7 vs 9.5 months; P = .808) in the subset of pts with SCC. This unplanned exploratory analysis examined outcomes in pts with SCC receiving > 4 cycles of nab-P/C to assess the feasibility of the nab-P/C regimen in the maintenance setting in SCC.

      Methods
      Pts with untreated stage IIIB/IV NSCLC were randomized 1:1 to nab-P 100 mg/m[2] on days 1, 8, 15 or sb-P 200 mg/m[2] on day 1 every 21 days; both arms received C AUC 6 on day 1. Overall response rate and progression-free survival (PFS) were determined by blinded centralized review. To allow comparison of the results of this analysis with maintenance studies, PFS is expressed from day 1 of cycle 5 (C5D1).

      Results
      229 pts with SCC received nab-P/C and 221 received sb-P/C in this study. In the nab-P/C arm, 60% (n = 138) of pts with SCC were progression-free at the end of cycle 4 and entered cycle 5 (the study population). In these pts, the median PFS was 3.4 months (range 2.8 – 4.2) from C5D1. The median OS from randomization in these pts was 13.8 months (range 12.4 – 16.8). Survival at 1year was 59% (51% – 67%). The median number of treatment cycles was 7 (range 5 – 31). A total of 125 (91%), 64 (46%) and 35 (25%) pts were treated for up to 6, 8 and 10 cycles, respectively, with a median weekly dose of 75 mg/m[2 ]for nab-paclitaxel in each group, and carboplatin AUC of 6, 4.75, and 4.5, respectively. Preliminary safety findings in this population revealed that the most common grade 3/4 treatment-related adverse events were neutropenia (49%), anemia (31%), and thrombocytopenia (27%). The overall rate of grade 3 peripheral neuropathy in the nab-P/C arm was 4% (with no grade 4); 1%, 3%, and 0% of pts had grade 3 peripheral neuropathy at cycle 6, 8, and 10, respectively.

      Conclusion
      Continued treatment with nab-P/C to progression was feasible, well tolerated, and effective in pts with advanced SCC who had not progressed after 4 cycles of first-line therapy. Future randomized, prospective studies are warranted to further evaluate the activity of nab-P/C as maintenance therapy in SCC pts.

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

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P1.10-018 - nab-Paclitaxel in combination with carboplatin as first-line therapy in patients with advanced non-small cell lung cancer (NSCLC): analysis of peripheral neuropathy (ID 1022)

      09:30 - 16:30  |  Author(s): M.F. Renschler

      • Abstract

      Background
      Peripheral neuropathy (PN) is a common side effect associated with taxane treatment. In a phase III trial, nab-paclitaxel (nab-P, 130 nm albumin-bound paclitaxel particles) + carboplatin (C) vs solvent-based paclitaxel (sb-P) + C significantly improved ORR (primary endpoint; 33% vs 25%; P = 0.005), with a trend toward improved OS and PFS in patients with advanced NSCLC. Here, we report on the PN profile of nab-P/C vs sb-P/C.

      Methods
      Patients with untreated stage IIIB/IV NSCLC were randomized 1:1 to nab-P 100 mg/m[2] on d 1, 8, 15 or sb-P 200 mg/m[2] q 1 q21d; both arms received C AUC 6 day 1 q21d. PN was assessed by Standardized MedDRA Query (SMQ) for neuropathy (broad scope) unless otherwise indicated. Patient-reported taxane-related neuropathy symptoms were assessed by the Functional Assessment of Cancer Therapy (FACT)-Taxane Additional Concerns scale.

      Results
      nab-P/C was associated with significantly less PN vs sb-P/C (all grade: 46% vs 62%; P < 0.001) and grade 3/4 treatment-related PN (3% vs 12%; P < 0.001). Grade 4 PN occurred in 2 patients in the sb-P/C arm vs 0 patients in the nab-P/C arm. PN led to taxane dose reductions in 2% vs 7% and delays in 3% vs 8% of patients in the nab-P/C vs sb-P/C arm. Physician assessment of PN based on NCI CTCAE grade showed fewer instances of worsening with nab-P/C vs sb-P/C. At baseline, ≥ 95% of patients in both arms were assessed with grade 0 PN, but at final evaluation, significant treatment differences favoring the nab-P/C arm were observed, with fewer nab-P/C−treated patients shifting from grade 0 to grades 1-4 (38%) relative to the sb-P/C arm (58%; P < 0.001). Fewer patients receiving ≤ 6 cycles (median number of cycles = 6) in the nab-P/C vs sb-P/C arms experienced all-grade PN (41% vs 60%); 2% vs 10% of these patients experienced grade 3/4 PN (no patients in the nab-P/C arm experienced grade 4 PN). Median time to PN onset of any grade was longer with nab-P/C vs sb-P/C, 49 vs 38 days (P < 0.001); grade 2-4, 105 vs 78 days (P = 0.04) and grade 3/4, 121 vs 106 days (P = 0.723). The median time to improvement of grade 3/4 PN to grade 1 was 38 vs 104 days (P = 0.326) with nab-P/C vs sb-P/C. Patient-reported FACT-Taxane PN subscore at final evaluation also demonstrated a statistically significant treatment effect favoring nab-P/C (P < 0.001). Most patients completed the FACT-Taxane questionnaire at baseline (98%) and provided follow-up assessments (94%) at each cycle. Deterioration in patient-reported PN subscore at or after the development of grade 3/4 PN was lower for nab-P/C vs sb-P/C (median change from baseline 4.5 vs 10).

      Conclusion
      In this trial, nab-P/C was associated with lower rates PN compared with sb-P/C. PN occurred later during treatment with nab-P/C vs sb-P/C, and the majority of patients experienced improvement of PN symptoms within approximately 1 month. Patients receiving ≤ 6 cycles of therapy with nab-P/C had less PN compared with those receiving sb-P/C.

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      P1.10-044 - nab-Paclitaxel in combination with carboplatin as first-line therapy in diabetic patients with advanced non-small cell lung cancer (NSCLC) (ID 2446)

      09:30 - 16:30  |  Author(s): M.F. Renschler

      • Abstract

      Background
      Diabetes and other age-related comorbidities frequently occur together in patients with NSCLC and may affect treatment efficacy and tolerability. Several studies demonstrated that diabetic patients have worse outcomes than those without diabetes. Additionally, studies have suggested that metformin may enhance the effects of chemotherapy, leading to improved outcomes. In a phase III trial, nab-paclitaxel (nab-P, 130 nm albumin-bound paclitaxel particles) + carboplatin (C) significantly improved the primary endpoint of overall response rate (ORR) from 25% to 33% (P = 0.005), with a trend toward improved overall survival (OS) and progression-free survival (PFS) vs solvent-based paclitaxel (sb-P) + C in patients with advanced NSCLC. This exploratory analysis examined efficacy and safety outcomes in diabetic patients with advanced NSCLC.

      Methods
      Patients with untreated stage IIIB/IV NSCLC were randomized 1:1 to nab-P 100 mg/m[2] on d 1, 8, 15 or sb-P 200 mg/m[2] d 1 q21d; both arms received C AUC 6 d 1 q21d. ORR and PFS were determined by blinded, centralized review. P values for ORR were based on chi-square test, and those for OS and PFS were based on log-rank test. Multiple sensitivity analyses were performed to confirm treatment differences and to rule out confounding effects from other baseline covariates.

      Results
      31 patients in the nab-P/C and 30 patients in the sb-P/C arms were included in this analysis. Similar to the intent-to-treat (ITT) population, most diabetic patients were male (75%), white (62%), with ECOG PS 1 (79%), and stage IV disease (85%). In these patients, ORR for nab-P/C vs sb-P/C was 52% vs 27% (response rate ratio 1.935; P = 0.046), median PFS was 10.9 vs 4.9 months (HR 0.416; P = 0.016), and median OS was 17.5 vs 11.1 months (HR 0.553; P = 0.057). Treatment difference in PFS remained significant (P ≤ 0.026) after adjusting for baseline characteristics (including histology, region, stage, and age). For OS, region, stage, race, and age were not observed to be confounding factors on treatment effect. Metformin was concomitantly used in 29% and 37% of diabetic patients in the nab-P/C vs sb-P/C arms, respectively. The percentage of patients experiencing ≥ 1 adverse event (AE) was similar between the diabetic and ITT populations. Among diabetic patients, the most common grade 3/4 AEs in the nab-P/C vs sb-P/C arms were neutropenia (53% vs 55%), anemia (23% vs 10%), peripheral neuropathy (PN, 7% vs 23%), thrombocytopenia (20% vs 7%), and fatigue (7% vs 10%); differences were not statistically significant. Safety findings were similar to those observed in the ITT population; however, the incidence of grade 3/4 PN was slightly higher for both arms in the diabetic population compared with the ITT population (for nab-P/C vs sb-P/C, 3% vs 12%; P < 0.001).

      Conclusion
      In this analysis, nab-P/C demonstrated improved efficacy and was well tolerated in diabetic patients with advanced NSCLC. These findings warrant further study in a larger diabetic patient population. The relationship between the efficacy of nab-P and glucose level/metformin use also merits additional study.

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    P2.10 - Poster Session 2 - Chemotherapy (ID 207)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-038 - nab-Paclitaxel in combination with carboplatin as first-line therapy in patients with advanced non-small cell lung cancer (NSCLC): analysis of predictive factors (ID 2462)

      09:30 - 16:30  |  Author(s): M.F. Renschler

      • Abstract

      Background
      Identification of predictive factors is critical for appropriate selection of patients and chemotherapy regimen. In a phase III trial, nab-paclitaxel (nab-P, 130 nm albumin-bound paclitaxel particles) + carboplatin (C) vs solvent-based paclitaxel (sb-P) + C significantly improved ORR (primary endpoint; 33% vs 25%, P = 0.005), with a trend toward improved OS and PFS in patients with advanced NSCLC. nab-P/C vs sb-P/C was associated with less severe peripheral neuropathy, arthralgia, and myalgia, but more anemia and thrombocytopenia. This exploratory analysis examined the correlation between several key patient and clinical factors and clinical outcomes with nab-P/C vs sb-P/C.

      Methods
      Patients with untreated stage IIIB/IV NSCLC were randomized 1:1 to nab-P 100 mg/m[2] on d 1, 8, 15 or sb-P 200 mg/m[2] d 1 q21d; both arms received C AUC 6 d 1 q21d. ORR and PFS were assessed by blinded, centralized review. P values for ORR were based on chi-square test, and those for OS and PFS were based on log-rank test. Factors, including sex, age (< 70 and ≥ 70 y), histology (squamous and nonsquamous), stage (IIIB/IV), and geographic region (North America, Eastern Europe, and Asia/Pacific), baseline ECOG score, smoking status, diabetes, body mass index, number and location of metastatic sites, were analyzed for association with outcomes; of these, the first 5 were prespecified stratification factors for the trial.

      Results
      The hazard ratio (HR)/risk ratio favored nab-P/C for ORR, PFS, and OS for most factors analyzed. Significant quantitative treatment-by-predictive factor interactions were noted for several key factors, including number of metastatic sites, diabetes, histology, and age, with respect to outcomes, and the comparative treatment effect was maintained in all other subgroups. In patients with ≥ 4 metastatic sites, significant treatment differences favoring nab-P/C were noted for ORR (response rate ratio [RRR] 3.40; P = 0.003) and OS (HR 0.562; P = 0.009) and trended in favor of nab-P/C for PFS (HR 0.735; P = NS). In patients with diabetes, significant treatment differences favoring nab-P/C were noted for ORR (RRR 1.935; P = 0.046) and PFS (HR 0.416; P = 0.016) and trended in favor of nab-P/C for OS (HR 0.553; P = NS). In patients with squamous NSCLC, significant treatment differences favoring nab-P/C were noted for ORR (RRR 1.68; P < 0.001) and trended in favor of nab-P/C for OS (HR 0.890; P = NS). In patients ≥ 70 y, significant treatment differences favoring nab-P/C were noted for OS (HR 0.583; P = 0.009) and trended in favor of nab-P/C for ORR (RRR 1.385; P = 0.196) and PFS (HR 0.687; P = NS). No treatment differences significantly favoring sb-P/C were observed.

      Conclusion
      A trend toward improved outcomes was noted with nab-P/C vs sb-P/C in most factors analyzed. Squamous NSCLC, diabetes, age ≥ 70 y, and ≥ 4 metastatic sites were predictive of improved outcomes with nab-P/C vs sb-P/C. These predictive factors should be taken into consideration when selecting the appropriate treatment for patients with advanced NSCLC.

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    P3.10 - Poster Session 3 - Chemotherapy (ID 210)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.10-043 - nab-Paclitaxel in combination with carboplatin as first-line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC): an economic analysis (ID 2479)

      09:30 - 16:30  |  Author(s): M.F. Renschler

      • Abstract

      Background
      In a phase III trial in first-line, advanced NSCLC, nab-paclitaxel + carboplatin (nab-P/C) significantly increased tumor response rates, with comparable overall survival (OS) vs solvent-based paclitaxel + carboplatin (sb-P/C). However, nab-P/C improved OS in prespecified, stratified subgroups of pts, including those aged ≥­ 70 y (19.9 vs 10.4 mo; P = 0.009) and in North American pts, (12.7 vs 9.8 mo; P = 0.008). Based on the data from this trial, nab-P/C was approved by the US Food and Drug Administration (FDA) as a first-line treatment in advanced NSCLC, a condition for which no drug has demonstrated a clinically meaningful survival advantage vs platinum doublets in an unselected population in FDA registration trials. Here, we report results of a cost-effectiveness analysis that was conducted from the US payer perspective, with resource use data collected during the trial.

      Methods
      Cost-of-care estimates were applied to patient-level data on chemotherapy, drug delivery, patient monitoring, supportive care drugs, and treatment of dose-limiting toxicity. Cost-effectiveness outcomes were presented as incremental cost per life year ($/LY) gained with nab-P.

      Results
      Use of colony stimulating factors and treatment discontinuations due to toxicity were comparable between experimental and control arms. Taxane dose intensity was higher with nab-P vs sb-P (79.6% vs 61.8%). For all pts, the nab-P/C group had a $25,868 higher cost compared with sb-P/C ($35,179 vs $9,310) and an incremental $/LY gained in excess of $100K, comparable with $/LY gained estimates published for other recently approved NSCLC agents. However, in the subsets of pts aged ≥ 70 y and those from North America, the cost differential was reduced to $18,244 and $19,941, respectively. $/LY gained was reduced to $23,000 and $83,000, respectively, which compares favorably with published incremental $/LY gained for other NSCLC agents based on their OS advantage in patient subpopulations. Similar results were observed in a post hoc analysis of the subgroup of pts aged ≥ 60 y.

      Conclusion
      Weekly nab-P/C can be considered a clinically and economically attractive treatment option for US payers for first-line advanced NSCLC, particularly in the North American and elderly subsets. Future clinical trials are needed to validate these findings.