05/21/2017: Articles Summaries - Breast & Lung Cancers

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BREAST CANCERS

Efficacy and safety of low-dose capecitabine plus docetaxel versus single-agent docetaxel in patients with anthracycline-pretreated HER-2 negative metastatic breast cancer: Results from the randomized phase III JO21095 trial
Yamamoto, D et al., Breast Cancer Res Treat. 2017 Feb;161(3):473-482.
PubMed ID: 28005247

Introduction:

Combination treatment in metastatic breast cancer remains controversial due to significantly high rates of adverse events compared to monotherapy. A few trials attempted to explore modified regimens using combination chemotherapy at reduced doses. Japanese researchers investigated the efficacy of dose reduced capecitabine-docetaxel vs. docetaxel alone in metastatic HER-2 negative breast cancer.

Methods:

  • Patients: histologically or cytologically confirmed metastatic HER-2 negative breast cancer that progressed during or after previous anthracycline-based chemotherapy (neoadjuvant or 1st line metastatic setting), ECOG 0-1; prior 5-FU or taxane allowed if completed ≥ 12 mos. prior to study entry
  • Study design: phase III open-label RCT
  • Intervention:
  • Experimental:
    • Concurrent XT Capecitabine 825 mg/m2 PO BID day 1-14 q3w
      • Docetaxel 60 mg/m2 IV q3w
  • Control:
    • Sequential TX
    • Docetaxel 70 mg/m2 IV q3w followed (at progression by) Capecitabine 1,250 mg/m2 PO BID day 1-14 q3w
  • Endpoints:
    • Primary: PFS
    • Secondary: OS, ORR, time to response (TTR), time to treatment failure (TTF), safety, QOL

Results:

  • 163 patients randomized to XT (n=82) and T (n=81)
  • 40% (32/81) received sequential capecitabine after progression on docetaxel.
  • Baseline patient characteristics: median age 56.5 yrs., 78% hormone receptor positive, 82% ECOG 0, 73% prior hormonal therapy, (59% adjuvant), 42% prior taxane, 86% ≥ 3 metastatic sites, 52% bone metastases

TABLE 1: EFFICACY OUTCOMES
Table 1

TABLE 2: ADVERSE EVENTS AND TREATMENT SUMMARY
Table 2

  • Safety
    • Most common grade ≥ 3 adverse event in both arms was hematologic (especially neutropenia).
    • More common with XT: grade ≥ 3 hand-foot syndrome
    • More common with T: grade ≥ 3 fatigue/malaise, peripheral edema
  • QOL
    • QOL was comparable in both arms, although a trend towards less deterioration over time was observed with XT.

Discussion:

  • At a median follow-up of 18 mos., low-dose XT provided marginal PFS advantage compared to docetaxel alone in metastatic HER-2 negative breast cancer after progression on anthracycline-based chemotherapy. OS was similar for XT and docetaxel monotherapy.
  • In a phase III trial that randomized women with HER-2 negative metastatic breast cancer to capecitabine-docetaxel (1,250/75 mg/m2) vs. docetaxel alone (100 mg/m2), combination treatment improved TTP (6.1 vs. 4.2 mos., HR 0.652; p=0.0001) compared to docetaxel (J Clin Oncol 20:2812-2823). OS was 14.5 vs. 11.5 mos., respectively (HR 0.775; p=0.0126). In this study, 40% were hormone positive, 67% had ≥ 3 metastatic sites and 58% received study drug in 2nd line. Adverse event rates were significantly increased with combination therapy (grade 3 adverse events 71% vs. 49%); dose reductions were reported in 65% vs. 36%, respectively.
  • In the TX arm, 40% received sequential capecitabine after progression on docetaxel. Median PFS was similar with XT in this group, suggesting PFS benefit with sequential treatment. However, due to small patient numbers, this post hoc analysis is merely hypothesis-generating.
  • Toxicity profile for treatment regimens in the trial was consistent with that known in the literature. Adverse events were observed in similar frequency in both treatment arms. No treatment-related deaths were reported. Combination treatment did not appear to compromise QOL compared to monotherapy.
  • This trial suggests that dose-reduced XT combination provided good clinical efficacy, with less toxicity compared to the full-dose regimen, even when 67% of the population required further dose adjustments. The benefit was observed in hormone receptor positive women with good performance status, more than 80% of who had ≥ 3 metastatic sites and almost half received hormonal therapy. The sequential use of capecitabine after progression on docetaxel is an attractive treatment strategy. However, this warrants further investigation in larger trials. Furthermore, sequencing of chemotherapy regimens in metastatic breast cancer has still not been established..

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LUNG CANCERS

Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial
Hanna, N et al. Lung Cancer. 2016 Dec;102:65-73.
PubMed ID: 27987591

Introduction:

Nintedanib is an angiokinase inhibitor that targets VEGFR, PDGFR and FGFR. In the LUME-lung 1 trial, nintedanib with docetaxel significantly prolonged PFS compared to docetaxel alone (3.4 vs. 2.7 mos., HR 0.79; p=0.0019) in advanced NSCLC (Lancet Oncol. 15 (2014) 143–155). Studies also suggest antitumor activity with pemetrexed and nintedanib, prompting investigators to explore this in the LUME-Lung 2 trial.

Methods:

  • Patients: histologically or cytologically-proven stage IIIB/IV or recurrent non-squamous NSCLC after failing at least 1 line of chemotherapy (excluding adjuvant/neoadjuvant treatment for recurrent disease), ECOG 0-1, no active brain metastases, no RT within the past 3 mos. prior to study
  • Study design: phase III double-blind, placebo-controlled RCT
  • Intervention:
  • Experimental:
    • Nintedanib 200 mg PO BID d2-21 q3w
    • Pemetrexed 500 mg/m2 IV d1 q3w
  • Control:
    • Pemetrexed 500 mg/m2 IV d1 q3w + Placebo
  • Endpoints:
    • Primary: PFS
    • Secondary: OS, ORR, DCR, safety, QOL

Results:

  • 713 patients randomized to nintedanib-pemetrexed (n=353) and pemetrexed-placebo (n=360)
  • Baseline patient characteristics: median age 59 yrs., 56% males, 61% ECOG 1, 53% ex-smokers, 3.5% EGFR mutation positive, 75% EGFR mutation unknown, 64% stage IV, 93% adenocarcinoma, 25% previous surgery, 97% previous platinum chemotherapy, 43% stable disease on first line therapy

TABLE 1: EFFICACY OUTCOMES
Lung Table 1

  • Subgroup analysis revealed similar improvement in PFS with nintedanib-pemetrexed compared to pemetrexed-placebo in the adenocarcinoma subgroup.
  • Safety
    • Most common any grade adverse events with nintedanib-pemetrexed: increased ALT (42.9%), increased AST (37.2%), nausea (36.9%), diarrhea (36.9%)
    • Most common grade ≥ 3 adverse events with nintedanib-pemetrexed: increased ALT (23.3%), decreased neutrophils (12.4%), increased AST (12.1%)
    • Most common any grade adverse events with pemetrexed-placebo: fatigue (36.4%), decreased appetite (25.2%), increased ALT (24.4%), vomiting (20.2%)
    • Most common grade ≥ 3 adverse events with pemetrexed-placebo: increased ALT (7.4%), decreased neutrophils (7.3%), fatigue (6.7%)
    • Adverse events specific to antiangiogenic agents (hypertension, bleeding, thrombosis) occurred in similar frequency in both arms.

TABLE 2: ADVERSE EVENTS AND TREATMENT SUMMARY
Lung Table 1

 Discussion:

  • Long-term follow-up confirmed the initially reported PFS benefit (1.2 mos. difference) with nintedanib-pemetrexed compared to pemetrexed-placebo in advanced NSCLC. Improvement in PFS however did not translate to OS advantage.
  • Adverse events increased with the addition of nintedanib to pemetrexed although serious adverse events, antiangiogen-specific side effects and rates of treatment discontinuation were similar in both arms. Elevated transaminases were commonly reported in the nintedanib-pemetrexed arm but were manageable with dose reductions.
  • The study was prematurely terminated because pre-planned futility analysis revealed low likelihood for the study to reach the predefined efficacy criteria. Furthermore, 75% of the study population had unknown EGFR mutation status. Patients who may have had EGFR mutation positive tumors would have received targeted therapy instead of chemotherapy based on current guidelines.
  • In summary, nintedanib with pemetrexed provided a trend towards PFS advantage that is unlikely clinically meaningful given that no OS benefit was found. The cost of treatment and significant adverse events compared to pemetrexed alone is considerable and could potentially limit its use in clinical practice. Also, pemetrexed is now often used in the first-line setting in combination with platinum which also reduces the clinical applicability of this study. However, LUME 3 a randomized phase 3 trial of nintedanib with docetaxel vs docetaxel did report an improvement of OS in advanced NSCLC adenocarcinoma subypte of of 12.6 months vs 10.3 months, 0=0.036. With current trials that demonstrated significant survival benefit with PD-L1 and PD-1 inhibitors, nintedanib may well be a less favoured treatment option in advanced NSCLC.. 

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