Improved outcomes for advanced non-small cell lung cancer

The chemotherapy agent Abraxane (nanoparticle albumin-bound (nab-) paclitaxel)TM, in combination with carboplatin, has been determined through a randomised phase III trial to be an effective first-line therapy for advanced non-small cell lung cancer (NSCLC), particularly squamous cell disease.1 The findings of this trial were presented by Associate Professor Peter Ellis and Dr Tom John at the Best of ASCO (American Society of Clinical Oncology) 2010 Australia conference in Sydney.2

NSCLC is the fourth most commonly diagnosed cancer in Australia, with over 8,000 new cases each year.³ While modest progress has been made on NSCLC treatments, there is great need for improvement.⁴ The phase III trial was led by principal investigator Mark Socinski, MD, at the University of North Carolina Lineberger Comprehensive Cancer Center, and is recognised as one of the largest NSCLC clinical studies to be conducted. 

Patients in the international, multicentre trial were randomised into an experimental treatment arm receiving nab-paclitaxel (100 mg/m²) weekly, with carboplatin (AUC 6) on day one of a three week treatment cycle (nab-P/C). Those randomised into the control treatment arm were premedicated with dexamethasone and antihistamines, then received solvent-based paclitaxel (200 mg/m²) every three weeks and carboplatin (AUC 6) on day one of a three week treatment cycle (P/C).¹

The trial found that nab-P/C demonstrated a significantly higher response rate than P/C (33% vs. 25%, p = 0.005). Of particular significance was the response rate in the squamous cell subset, which was 41% in the nab-P/C arm vs. 24% in the P/C arm (p < 0.001). There was no statistically significant difference in response rates (ranging from 25% to 37%) between P/C and nab-P/C in patients with non-squamous histology.¹

It should be noted that response based on histology was not a pre-specified endpoint for this trial. The primary endpoint was objective response rate as assessed by independent radiologic review based on RECIST (Response Evaluation Criteria In Solid Tumours). Secondary endpoints included progression-free and overall survival, disease control rate, and safety (NCI common terminology criteria for adverse events, v3).¹

Socinski said:

“This is exciting news for lung cancer patients and has important implications not only in late stage cancer but also in earlier stages of the disease.”

Abraxane is a nanoparticle albumin-bound (nab) agent that has an established role in the treatment of metastatic breast cancer. Albumin is used to deliver the active ingredient to tumour sites. As it is a naturally occurring protein, using albumin eliminates the need for a solvent. The significant variation in mechanism of action between the two paclitaxel formulations – nab-paclitaxel and solvent-based paclitaxel – presents nab-paclitaxel as a more bioavailable treatment that eliminates the risk of hypersensitivity reactions and potential anaphylaxis due to the solvent. This allows a 49% higher dose of paclitaxel to be systemically absorbed.⁵ Previous studies conducted in metastatic breast cancer have shown that nab-paclitaxel almost doubles the tumour response rate compared with solvent-based paclitaxel. It has not displayed significant differences in safety or tolerability.⁶

In the lung cancer trial, nab-P/C was associated with a 70% reduction in neuropathy compared with P/C (3% vs. 10% respectively). Of the statistically significant events, neutropaenia (11% vs. 22%) and myalgia (<1% vs. 2%) were less common with nab-P/C.⁷ Conversely, anaemia (5% vs. 1%) and thrombocytopenia (5% vs. 1%) were more common in the nab-P/C treatment arm than the P/C arm. There was no significant difference in rates of febrile neutropaenia, fatigue, anorexia or nausea. No hypersensitivity reaction occurred in the nab-P/C arm without prophylactic premedication, while three cases occurred in the P/C arm.¹

Inclusion criteria for the study were histologically or cytologically confirmed stage IIIb/IV NSCLC, ECOG performance status of 0 or 1, measurable disease by RECIST, chemotherapy naivety, and adequate haematological, hepatic and renal function. Patients were excluded from the study if they had active brain metastases or significant baseline peripheral neuropathy. The participants were stratified for stage of disease (IIIb vs. IV), age (<70 vs. >70), gender, histology (squamous vs. non-squamous) and geographic region.¹

The 1,052 patients were enrolled for this study from the US (12%, 25 sites), the Ukraine (24%,16 sites), Russia (45%, 29 sites), Japan (12%, 21 sites), Canada (4%, 6 sites) and Australia (1%, 5 sites). The median age of patients in the study was 60 years, with a range of 24 to 84 years. A quarter of the subjects were female. One in five patients were stage IIIb at current diagnosis, with remaining subjects stage IV. 27% of the patients had never smoked, 30% had smoked and quit, 43% of patients still smoked. In terms of primary diagnosis, 49% were identified as having adenocarcinoma, 43% squamous cell carcinoma, 2% large cell carcinoma, and 6% other.⁷

The authors plan to analyse progression-free survival later this year. The proposed follow-up period for this trial is 18 months.¹

References

1. Socinski MA, Bondarenko IN, Karaseva NA, et al. Results of a randomized, phase III trial of nab-paclitaxel (nab-P) and carboplatin (C) compared with cremophor-based paclitaxel (P) and carboplatin as first-line therapy in advanced non-small cell lung cancer (NSCLC). Abstract No. LBA 7511. Originally presented at: The 2010 American Society of Clinical Oncology (ASCO) Annual Meeting; Chicago IL; 4-8 June 2010. Re-presented at: The 2010 Best of ASCO (American Society of Clinical Oncology) Australia conference; Sydney NSW; 14 August 2010. Available from: URL link
2. 2010 Best of ASCO® Meeting Program [online]. Sydney, NSW: Best of ASCO® Australia Expert Committee; 2010 [cited Aug 2010]. Available from: URL link
3. Incidence and prevalence of chronic diseases [online]. Canberra, ACT: Australian Institute of Health and Welfare; 2006 [cited June 2010]. Available from: URL link
4. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542-50. [Abstract | Full text]
5. Product Information: Abraxane. East Kew, VIC: Abraxis BioScience Australia Pty Ltd; 29 September 2008. Available from: URL link
6. Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005;23(31):7794-803. [Abstract | Full text]
7. Socinski MA, Results of a randomized, phase III trial of nab-paclitaxel (nab-P) and carboplatin (C) compared with cremophor-based paclitaxel (P) and carboplatin as first-line therapy in advanced non-small cell lung cancer (NSCLC). Abstract No. LBA 7511. [Presentation slides]. Presented at the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting; Chicago IL; 4-8 June 2010. Available from: URL link