Amy Ko

CA19-9 decrease at 8 weeks as a predictor of overall survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic pancreatic cancer

Any CA19-9 decline at week 8 and radiologic response by week 8 each predicted longer OS in both treatment arms. In the nab-P + Gem arm, the higher proportion of patients with week 8 CA19-9 decrease [82% (206/252); median OS 13.2 months] than a RECIST-defined response [16% (40/252); median OS 13.7 months] suggests that CA19-9 decline is a predictor of OS applicable to a larger population.

Abstract OT1-01-07: nab-paclitaxel (nab-P) plus nivolumab (Nivo) in human epidermal growth factor receptor 2 (HER2)–negative recurrent metastatic breast cancer (MBC)

Background: Nivo is an inhibitory antibody against programmed death receptor-1 (PD-1), a regulator of antitumor immunity. Nivo is approved for treatment of unresectable or metastatic melanoma and disease progression (PD) following ipilimumab or, in BRAF V600 mutation–positive melanoma, following a BRAF inhibitor, and for metastatic squamous non-small cell lung cancer (NSCLC) following PD during or after platinum-based chemotherapy. Nivo and other immune checkpoint inhibitors are also being investigated in other tumor-types. nab -P is a novel taxane formulation and does not require prophylaxis with immunosuppressive steroids. It has demonstrated superior efficacy over control regimens in phase III studies of MBC, pancreatic cancer, and NSCLC. This open-label, 6-arm, multicenter phase I trial will evaluate the safety of Nivo with nab -P in 3 cancer types (2 arms/disease): MBC, advanced NSCLC (+ carboplatin), and advanced pancreatic cancer (± gemcitabine). The study design for the MBC portion is described below. Methods : Eligibility criteria include histologically/cytologically confirmed HER2-negative MBC; 1 prior chemotherapy for MBC, including an anthracycline unless clinically contraindicated; no relapse nab -P 100 mg/m2 on days 1, 8, and 15 of each 28-day cycle plus Nivo 3 mg/kg on days 1 and 15 starting at cycle 3 or nab -P 260 mg/m2 on day 1 of each 21-day cycle plus Nivo 5 mg/kg on day 15 starting at cycle 3. Pts will be treated until PD or allowed to continue treatment beyond RECIST v1.1–defined PD if they continue to meet study eligibility; do not have rapid PD or clinical deterioration or unacceptable toxicities; and can benefit from continuation of study treatment in the treating physician9s opinion and will not delay an imminent intervention to prevent serious complications of PD. The primary endpoints of the study are the number of pts with dose-limiting toxicities (DLTs) in each treatment arm (part 1) and the percentage of pts with grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to a TEAE (parts 1 and 2). Part 1 of the study will assess whether the starting dose of Nivo is deemed safe (≤ 1 DLT in 6 pts); otherwise, the Nivo dose will be de-escalated and assessed in a new cohort at the next lower dose level. The Nivo dose in combination with nab -P deemed safe in a treatment arm may be further assessed in part 2 of the study, with enrollment expanded to an additional ∼ 14 pts/arm (total of 20 Nivo-treated pts/arm). Secondary study endpoints include TEAEs leading to dose reduction, delay, interruption, or treatment discontinuation; progression-free survival; overall survival; disease control rate; overall response rate; and duration of response (per RECIST v1.1). Exploratory endpoints include tumor-associated PD-L1 expression, modulation of immune activation in the tumor and peripheral blood in response to Nivo treatment, Nivo serum levels, and development of anti-globulin antibodies. ClinicalTrials.gov identifier NCT02309177. Citation Format: Waterhouse D, Gutierrez M, Bekaii-Saab T, DeRosa W, Wainberg Z, George B, Duval Fraser C, Ko A, Pierce DW, Stergiopoulos S, Soliman H. nab -paclitaxel ( nab -P) plus nivolumab (Nivo) in human epidermal growth factor receptor 2 (HER2)–negative recurrent metastatic breast cancer (MBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-01-07.

P1.46: Phase I Study of Nivolumab + Nab-Paclitaxel in Solid Tumors: Preliminary Analysis of the Non-Small Cell Lung Cancer Cohort: Track: Advanced NSCLC

by 10 mg decrements to a minimum of 20 mg/day. The incidence and severity of common AEs before and after dose reduction were analyzed, and PK data collected during the standard visit schedules on Days 22 and 43 was compared in patients who reduced to 30 mg versus those remaining at 40 mg/day. PFS in patients who dose reduced within the first 6 months of treatment was compared with those who remained on 40 mg/day. Results: Dose reductions occurred in 53% (122/229) of patients in LL3 and 28% (67/239) of patients in LL6. The majority (LL3: 86%; LL6: 82%) of dose reductions occurred within the first 6 months of treatment. Dose reduction led to decreases in incidence and severity of EGFR-mediated drug-related AEs across LL3 and LL6 (Table). A combined PK analysis of LL3 and LL6 suggested that dose reduction was more likely in patients with higher afatinib plasma concentrations. Patients who dose reduced to 30 mg had geometric mean plasma afatinib concentrations of 45.6 ng/mL on Day 22 (n1⁄422) and 23.3 ng/mL on Day 43 (n1⁄459), compared with those who remained on 40 mg with concentrations of 24.3 ng/ mL on Day 22 (n1⁄4282) and 22.8 ng/mL on Day 43 (n1⁄4284). Across LL3 and LL6, median PFS was similar in patients who dose reduced during the first 6 months of treatment versus those who remained on 40 mg/day (LL3: 11.3 vs 11.0 months, HR1⁄41.25 [95% CI: 0.91e1.72]; LL6: 12.3 vs 11.0 months, HR1⁄41.00 [95% CI: 0.69e1.46]). Conclusion: In LL3 and LL6, afatinib demonstrated a trend towards improved overall survival (OS) versus chemotherapy in the overall study populations and significant OS improvements in patients with EGFR Del19positive disease. Results from this post-hoc analysis indicate that tolerability-guided dose adjustment of afatinib reduces treatment-related AEs without adversely affecting efficacy.

P1.48: nab-Paclitaxel + Carboplatin in Advanced Non-Small Cell Lung Cancer: Outcomes in Elderly Patients With Squamous Histology: Track: Advanced NSCLC

LCSS, average total score & symptom burden index improved during induction chemotherapy; a higher percentage of Rs vs non-Rs had clinically meaningful improvements ( 10 mm [VAS]) from BL in composite LCSS cough, shortness of breath, & hemoptysis (56% vs 38%). Of pts reporting BL EQ-5D-5L dimension problem(s), a higher percentage of Rs vs non-Rs reported complete resolution of symptoms at least once during treatment (Table). Conclusion: These results indicate that Rs & non-Rs maintained/improved QoL during induction therapy with nab-P/C. Rs appeared to have greater improvements in LCSS & EQ-5D-5L. Radiological response translates into meaningful QoL improvement. NCT02027428

Quality of life (QoL) by response: An interim analysis of patients (pts) with squamous (SCC) NSCLC treated with nab-paclitaxel/carboplatin (nab-P/C) induction therapy in the phase III ABOUND.sqm study.

63 Background: The correlation of radiological response and pt-reported outcomes (PROs) in advanced NSCLC remains underreported. This interim analysis evaluated QoL by response (RECIST v1.1) in SCC NSCLC pts treated with nab-P/C during the induction part of the ABOUND.sqm study. METHODS In the ongoing phase III ABOUND.sqm study, pts with advanced SCC NSCLC are treated with first-line nab-P 100 mg/m2 d 1, 8, 15 and C AUC 6 mg•min/mL d 1 (21-d cycles) for 4 cycles (induction). Pts not progressing are randomized 2:1 to maintenance nab-P 100 mg/m2d 1 and 8 of each 21-d cycle + best supportive care (BSC) or BSC alone until progression. The primary endpoint is PFS from randomization to maintenance. QoL, an exploratory endpoint, was assessed with predefined PRO instruments, LCSS and EQ-5D-5L, on d 1 of each cycle. Pts with a radiological CR/ PR are considered responders (R) in this analysis (57% of evaluable pts). As the study is ongoing, this pre-planned analysis included QoL and tumor response data that were reported up to the cutoff date. RESULTS Baseline (BL) characteristics were similar for Rs (n = 73) and non-Rs (n = 55). Over 80% of pts completed BL + ≥ 1 post-BL PRO assessments. For LCSS, average total score and symptom burden index improved during induction chemotherapy; a higher percentage of Rs vs non-Rs had clinically meaningful improvements (≥ 10 mm [VAS]) from BL in composite LCSS cough, shortness of breath, & hemoptysis (56% vs 38%). Of pts reporting BL EQ-5D-5L dimension problem(s), a higher percentage of Rs vs non-Rs reported complete resolution at least once during treatment (Table). CONCLUSIONS These results indicate that Rs and non-Rs maintained/improved QoL during induction therapy with nab-P/C. Rs appeared to have greater improvements in LCSS and EQ-5D-5L. Radiological response translates into meaningful QoL improvement. CLINICAL TRIAL INFORMATION NCT02027428. [Table: see text].

nab-Paclitaxel/carboplatin in elderly patients with advanced squamous non-small cell lung cancer: a retrospective analysis of a Phase III trial

Background Limited data on elderly patients with squamous advanced non-small cell lung cancer (NSCLC) preclude optimal treatment. Here, we report the outcomes of a retrospective analysis of a subset of patients ≥70 years with squamous histology from the Phase III trial that evaluated nab-paclitaxel/carboplatin vs paclitaxel/carboplatin. Patients and methods Patients with stage IIIB/IV NSCLC received (1:1) nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 or paclitaxel 200 mg/m2 on day 1, both with carboplatin area under the curve 6 mg×min/mL on day 1 every 3 weeks. The primary endpoint was independently assessed overall response rate as per the Response Evaluation Criteria in Solid Tumors v1.0. Secondary endpoints included progression-free survival, overall survival, and safety. Results Sixty-five patients ≥70 years with squamous histology were included (nab-paclitaxel/carboplatin, n=35; paclitaxel/carboplatin, n=30). nab-Paclitaxel/carboplatin vs paclitaxel/carboplatin, respectively, resulted in an overall response rate of 46% vs 20% (response rate ratio, 2.29, P=0.029) and a median overall survival of 16.9 vs 8.6 months (hazard ratio, 0.50, P=0.018). No difference was observed in median progression-free survival (5.7 months for both). Incidences of grade 3/4 neutropenia (50% vs 63%), leukopenia (29% vs 37%), fatigue (3% vs 13%), and peripheral neuropathy (3% vs 13%) were lower, but those of thrombocytopenia (21% vs 10%) and anemia (21% vs 7%) were higher with nab-paclitaxel/carboplatin vs paclitaxel/carboplatin. Conclusion nab-Paclitaxel/carboplatin was efficacious and tolerable in patients ≥70 years with squamous NSCLC. These results build upon prior analyses, indicating that nab-paclitaxel/carboplatin is effective for this difficult-to-treat patient subgroup.

Quality-Adjusted Survival With nab-Paclitaxel Versus Standard Paclitaxel in Metastatic Breast Cancer: A Q-TWiST Analysis

Background In this analysis we compared quality‐adjusted survival outcomes between nab‐paclitaxel (nab‐P) and standard paclitaxel (Pac) using data from the nab‐P phase III registration trial in metastatic breast cancer. Patients and Methods Quality‐adjusted overall survival was estimated using the quality‐adjusted time without symptoms or toxicity (Q‐TWiST) approach. Overall survival was partitioned into time without progression/Grade ≥ 3 adverse events (AEs) toxicity (TWiST), time with Grade ≥ 3 AE toxicity (TOX), and time after relapse (REL). Q‐TWiST was calculated by multiplying mean time in each health state by its assigned utility (base‐case utility values: time without symptoms of disease progression or toxicity of Grade ≥ 3 adverse events [TWiST] = 1.0, TOX = 0.5, and REL = 0.5). In threshold analyses, TOX and REL varied from 0.0 to 1.0 whereas TWiST was maintained at 1.0. Comparisons were made for the intent‐to‐treat population and the subset of patients initiating the study drugs as second or subsequent lines (2L+) of chemotherapy (per approved nab‐P indication; 2L+ subpopulation). A ≥ 15% relative Q‐TWiST gain (vs. mean Pac overall survival) was considered clearly clinically important. Results In the intent‐to‐treat population, nab‐P (n = 229) versus Pac (n = 225) resulted in nonsignificant gains of 1.4 months of mean Q‐TWiST (11.6 vs. 10.2 months; 95% confidence interval [CI], −0.03 to 2.8). In the 2L+ subpopulation, nab‐P (n = 132) versus Pac (n = 136) resulted in a statistically significant gain of 2.2 months of mean Q‐TWiST (10.5 vs. 8.4 months; 95% CI, 0.6‐3.8), with a 17.1% relative Q‐TWiST gain (threshold analysis range, 14.0%‐19.5%, both figures significant). Conclusion In its approved indication for metastatic breast cancer, nab‐P showed a statistically significant and clearly clinically important improvement in quality‐adjusted survival time versus Pac in the 2L+ subpopulation. Micro‐Abstract Evidence on quality‐adjusted survival between nab‐paclitaxel (nab‐P) and standard paclitaxel (Pac) in patients with metastatic breast cancer (MBC) is limited. Using a quality‐adjusted time without symptoms or toxicity approach, quality‐adjusted survival was evaluated in MBC patients receiving nab‐P or Pac in a phase III registration trial. Patients receiving nab‐P as second‐line or greater therapy had a statistically significant, clinically important improvement in quality‐adjusted survival versus those receiving Pac.

nab-paclitaxel/carboplatin induction in squamous NSCLC: Longitudinal quality of life while on chemotherapy

Background Longitudinal data on the impact of treatment on quality of life (QoL) in advanced non-small cell lung cancer (NSCLC) are limited. In this palliative setting, treatment that does not deteriorate QoL is key. Here we report longitudinal QoL in patients with squamous NSCLC, receiving ≤4 cycles of nab-paclitaxel/carboplatin combination chemotherapy. Methods Patients received nab-paclitaxel 100 mg/m2 days 1, 8, 15 + carboplatin area under the curve 6 mg•min/mL day 1 (q3w) for four cycles. QoL was assessed by the Lung Cancer Symptom Scale (LCSS) and Euro-QoL-5 Dimensions-5 Levels (EQ-5D-5L) at baseline and each cycle (day 1). Results Two-hundred and six lesion-response-evaluable patients completed baseline + ≥1 postbaseline QoL assessment and were QoL evaluable. LCSS average total score and symptom burden index improved from baseline throughout four cycles. In the LCSS pulmonary symptoms score, 46% of patients reported clinically meaningful improvement (≥10 mm visual analog scale) from baseline. Individual EQ-5D-5L dimensions remained stable/improved in ≥83% of patients; ≈33% reported complete resolution of baseline problems at least once during four cycles. Generally, responders (unconfirmed complete/partial response) had higher scores vs nonresponders. Conclusion In patients with squamous NSCLC, four cycles of nab-paclitaxel/carboplatin demonstrated clinically meaningful QoL improvements, with greater benefits in responders vs nonresponders.

Erratum to 'Phase II/III weekly nab-paclitaxel plus gemcitabine or carboplatin versus gemcitabine/carboplatin as first-line treatment of patients with metastatic triple-negative breast cancer (the tnAcity study): Study protocol for a randomized controlled trial. [Trials (2015), 16, 575] DOI: 10.1186/s13063-016-1195-6

Unfortunately, the original version of this article [1] contained a few formatting errors which have been corrected via an update. In the eighth paragraph of the background there was an error. The original read as, “A phase II study evaluating the combination of nabpaclitaxel plus carboplatin as 199 first-line treatment for mTNBC is currently under way [31].” But should have read as “A phase II study evaluated the combination of nab-paclitaxel plus carboplatin a first-line treatment for mTNBC [31].”

P1.47: ABOUND.sqm QoL by Response: Interim Analysis of Squamous NSCLC Pts Treated With nab-Paclitaxel/Carboplatin Induction Therapy: Track: Advanced NSCLC.

Method: The primary objective of part 1 is to evaluate dose-limiting toxicities (DLTs). Patients (pts) treated with 2 cycles of nivo with chemotherapy (CT) and remained on study for 14 additional calendar days or who discontinued due to DLT prior to completing 2 cycles of nivo were considered DLT evaluable. Treatment arms could expanded in Part 2 to further assess safety, tolerability, and antitumor activity. The lung arms, C and D, were initiated sequentially in part 1 of the study. In Arm C, treatment-naive pts with stage IIIB/IV NSCLC received 4 cycles of nab-P 100 mg/m on days 1, 8, and 15 plus C AUC 6 on day 1 of a 21 day cycle in combination with nivolumab 5 mg/kg on day 15 starting at cycle 1. Enrollment for Arm D starts after Arm C is deemed safe to expand. The same regimen will be given in Arm D; however, nivolumab will be given starting cycle 3. In both NSCLC arms, nivo monotherapy begins at cycle 5.