Randomized, double-blind, placebo-controlled phase II study of carboplatin and paclitaxel with or without vorinostat, a histone deacetylase inhibitor (HDAC), for first-line therapy of advanced non-small cell lung cancer (NCI 7863)

Reviewer: Arpi Thukral, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 1, 2009

Presenter: Suresh. S. Ramalingam, MD
Presenter's Affiliation: Emory University
Type of Session: Scientific


  • Cells must control the coiling and uncoiling of DNA around histones to carry out gene expression. Histone acetylases are compounds that acetylate the lysine residues in core histones to create a less compact and more transcriptionally active chromatin.
  • Histone deacetylases (HDAC), on the other hand, remove the acetyl groups from the lysine residues leading to the formation of a condensed and transcriptionally silenced chromatin.
  • HDAC inhibitors (HDI) block this action and can result in hyperacetylation of histones, therefore affecting gene expression. They work on non-histone proteins to affect cellular regulation as well.
  • Vorinostat is a Class I and II HDAC inhibitor which has been approved for use by the FDA for cutananeous T cell lymphoma. It is administered orally.
  • A study by Traynor et. al. recently published in the J Thor Oncology in 2009 showed that Vorinostat was not active as monotherapy in relapsed NSCLC cancer patients. The authors of this study concluded that “no objective antitumor activity was detected with single agent vorinostat in this setting; however, it yielded TTP in relapsed NSCLC similar to that of other targeted agents. Further studies in NSCLC should focus on combining vorinostat with other antitumor agents.”
  • Preclinical studies have shown that Vorinostat can increase the efficacy of taxanes by inhibition of HDAC causing enhanced tubulin acetylation and can increased the efficacy of platinum agents by enhancing DNA fragmentation.
  • The authors of this study have seen previous promising results with carboplatin (C), paclitaxel (P), and vorinostat in patients with advanced NSCLC in the a phase I study (Ramalingam et al, Clin Cancer Res, 2007). They observed objective responses in 10/19 patients enrolled in the Phase I study.
  • The earlier Phase I work by this group provided the rationale for the current placebo-controlled, randomized phase II study comparing response rates in patients receiving Vorionstat verus placebo in advanced NSCLC patients receiving treatment with Carboplatin and Pacliataxel.

Materials and Methods

  • The primary objective of this study was to compare response rate (RR) associated with patients receiving Paclitaxel and Carboplatin (PC) with either Vorinostat or placebo.
  • The secondary objective was to examine and compare progression-free-survival (PFS), overall survival (OS), and toxicity data in the two groups.
  • Eligibility criteria:
    • Patients with stage IIIB (wet) or IV NSCLC.
    • No prior chemotherapy.
    • Age > 18.
    • ECOG performance status (PS) 0/1
    • Patients had to have measurable disease.
    • Adequate bone marrow, renal and hepatic function
  • Patients were randomized (2:1) for therapy with PC with either vorinostat or placebo.
    • Treatment consisted of C: AUC=6 mg/ml.min; and P 200 mg/m2 both given on day 3 along with either vorinostat (400 mg PO QD) or placebo on days 1-14 of each 3 week cycle.
    • The maximum number of cycles allowed was 6. No crossover or maintanence therapy was allowed.
  • The primary endpoint of RR was measured by RECIST Criteria. The estimated sample size which was powered to 80% to demonstrate a 25-50% improvement in response rate for vorinostat over placebo was 93 pts. It was planned to accrue 7 patients per month.
  • The one-sided P, type I error was 10%.


  • Ninety-four patients were enrolled (vorinostat (V): n=64; placebo (P): n=32) on this study between May 2007 and June 2008.
  • Pts. baseline characteristics were well-balanced between the two arms. Females accounted for 39% of the V group and 38% of the P group. Median ages were 64 and 66 years, respectively in the 2 groups. The ECOG PS was also comparable between the 2 groups.
  • NSCLC NOS was the most common subtype in both groups, accounting for 42% of the histologies in the V group and 40% in the P group.
  • Median # cycles: V: 3.5; P: 4.
  • The confirmed response rate was superior with vorinostat over placebo (34% vs. 12.4%, p = 0.021).
  • The median PFS for vorinostat and placebo were 6.0 months and 4.1 months respectively; p=0.33, HR=0.79.
  • The median OS for vorinostat and placebo were 13 months and 9.7 months respectively; p=0.17, HR=0.67.
  • The 1-year survival rates were 53% for the V group and 35% for the P group.
  • Common grade 3/4 toxicities (vorinostat vs. placebo): neutropenia (44% vs. 47%); thrombocytopenia (33% vs. 16%); fatigue (13% vs. 3%); hyponatremia (21% vs. 6%); diarrhea (5% vs. 0). The only one of these toxicities which was statistically significant was Grade 4 thrombocytopenia which was higher in the Vorinostat group.
  • Discontinuation from study after cycle 1 was higher with vorinostat (27% vs. 16%).
  • Two treatment related deaths occurred in the experimental arm versus none in the control arm.

Author's Conclusions

  • Administration of vorinostat with carboplatin and paclitaxel resulted in a significantly superior response rate for patients with advanced NSCLC, for both squamous and non-squamous histologies.
  • The authors conclude that Vorinostat enhances the effectiveness of PC in patients with previously untreated advanced stage NSCLC.
  • However, improvement of toxicities associated with Vorinostat is required.
  • HDAC inhibition is a promising and novel therapeutic strategy for treatment of NSCLC and should be further studied in clinical trials.

Clinical/Scientific Implications

  • Advanced NSCLC is a debilitating disease with very low OS survival rates. It is imperative to improve our current chemotherapy regimens for this disease to improve outcomes. Adding novel agents such as HDAC inhibitors to standard chemotherapy is an exciting and promising area of research.
  • This trial represents a well-designed multi-center, phase II randomized study evaluating the effects of Vorinostat, an HDAC inhibitor, on response rates in patients with advanced NSCLC (Stage wet IIIB and IV). Arms were well-balanced.
  • Superior results were seen for the Vorinostat group compared to the placebo group for all of the outcomes measured, including RR, PFS, and OS. Although the results were only significant for RR, since the current study was not powered to show differences in PFS and OS.
  • Although this study provided a positive result, the authors did report that thromoboctyopenia and treatment related deaths were higher in the experimental group. It will be very important to study these toxicities in future trials before we start implementing this treatment in the clinic for our cancer patients.
  • The authors were able to show an improvement in RR in the treatment arm compared to the control arm. This provides an adequate impetus to proceed with this drug to Phase III studies. It will be interesting to see these results and hopefully, these future trials will allow us to identify criteria to select patients appropriately for this novel agent.
  • Future studies should also include biomarker studies on baseline tumor tissue and peripheral blood cells to help us to better understand the mechanism of action and selectivity of HDAC inhibitors, so new agents to treat lung cancer can be discovered and researched in upcoming trials.

See Patient Summary