Carlson, Robert H.
CHICAGO—Platinum-based doublets have been a mainstay in the treatment of advanced non-small-cell lung cancer for more than a decade, with overall response rates of 15% to 25%.
With that as a backdrop for his late-breaking report here at the ASCO Annual Meeting, Mark A. Socinski, MD, Professor of Medicine in the Multidisciplinary Thoracic Oncology Program at Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill, presented response and safety results from a multicenter, Phase III randomized study comparing nab-paclitaxel plus carboplatin with carboplatin plus the standard cremophor-based paclitaxel in first-line therapy of advanced NSCLC.
He said nab (nanoparticle albumin bound) paclitaxel was well tolerated, there was no need for premedication with it, and infusion time was 30 minutes vs three hours for standard paclitaxel.
Major Endpoint Was Response
The trial was unusual in that response was the major study endpoint. Dr. Socinski reported a statistically significant difference in response between the two study arms—33% for nab-paclitaxel plus carboplatin, vs 25% for paclitaxel-carboplatin.
Objective response rates by histology also differed. In an unplanned analysis, response rates for squamous cell carcinoma were 41% for nab-paclitaxel-carboplatin vs 24% for paclitaxel-carboplatin.
For non-squamous cell carcinoma, the rates were 26% and 25%, respectively.
The study population included chemo-therapy-naïve patients with Stages IIIb or IV NSCLC, with 525 randomly selected to receive nab-paclitaxel at 100 mg/m2 on Days 1, 8, and 15, with carboplatin on Day 1 to an area under the curve (AUC) of 6. These patients received no premedication.
Study Discussant RAF...Image Tools
Another 525 patients selected to receive paclitaxel 200 mg/m2 and carboplatin AUC 6, both on Day 1, received premedication with dexamethasone and antihistamines.
The hypothesis, Dr. Socinski explained, is that nab-paclitaxel leverages the GP60 caveolin-1 SPARC transcytosis pathway and establishes a portal to the tumor microenvironment—which results in higher intratumor drug concentrations.
SPARC—secreted protein acidic and rich in cysteine—regulates endothelial cell shape and barrier function, he said.
“Overexpression of caveolin-1 and SPARC is known to be associated with poor prognosis.” Nab-paclitaxel may have been more active in patients with squamous cell carcinoma because the tumors may be richer in caveolin-1, he said.
Less Peripheral Neuropathy
Patients treated with nab-paclitaxel -reported fewer toxicities commonly associated with cremophor-based paclitaxel, including peripheral neuropathy and serious hypersensitivity reactions.
In this trial, the 514 patients evaluable for toxicity in the nab-paclitaxel arm -reported less sensory neuropathy, three Grade 3 cases vs 10 for standard paclitaxel, compared with 524 evaluable patients in the paclitaxel arm. There were also fewer events of neutropenia and myalgias with nab-paclitaxel.
But patients receiving nab-paclitaxel had more Grade 4 neutropenia and more Grade 3/4 thrombocytopenia and anemia.
In his presentation, Dr. Socinski listed some limitations of this study, which were expanded upon by the session's Discussant, Raffit Hassan, MD, Senior Investigator and Head of the Solid Tumor Immunotherapy Section in the Laboratory of Molecular Biology at the National Cancer Institute.
“The major limitation was the use of response rate as primary endpoint,” Dr. Hassan said, also noting that evaluation of tumor response by histology was not a prespecified endpoint and that biomarkers of response were not incorporated in the study design. Clearly, we need data regarding progression-free survival and overall survival from this trial to see where [nab-paclitaxel] stands.”
Dr. Socinski answered that he believes response was an appropriate endpoint in this trial, because “in this setting, with an already approved drug, we are looking at a different formulation that is possibly more biologically active.
MARK A. SOCINSKI, MD...Image Tools
Why Did the Range of Cycles Per Patient Go Up to 22?
“Looking at response rate as well as survival is appropriate for this type of trial,” Dr. Socinski said.
Session co-moderator, Lecia Sequist, MD, Assistant Professor in the Department of Medicine at Harvard Medical School and an assistant physician at Massachusetts General Hospital, asked Dr. Socinski why the range of cycles per patient went up to 22 cycles in one case.
Dr. Socinski said the protocol was written by committee and that he had argued for a six-cycle limit, noting that he had stopped treating patients after six cycles.
The important data are yet to come, he said: The rates of overall and progression-free survival should be available by the end of the year.
“And we need to determine if tumor response, especially in squamous cell histology, correlates with SPARC expression,” he said.
© 2010 Lippincott Williams & Wilkins, Inc.