At-Risk Lung Cancer Patients Respond to Nab-Paclitaxel Regimen

CHICAGO – Combination therapy with nanoparticle albumin bound–paclitaxel and carboplatin may be an option for the subset of advanced non–small cell lung cancer patients who are ineligible for bevacizumab treatment because of bleeding risk.

The combined treatment produced an objective response rate of more than 40% among non–small cell lung cancer (NSCLC) patients with squamous histology or other hemorrhagic risk factors in a single-arm, single institution, phase II trial presented at the annual meeting of the American Association for Cancer Research.

The preliminary results, which include evidence of "tolerable toxicity," are especially encouraging because of the limited treatment options available to this patient population, according to the senior investigator Dr. Gregory Otterson of the Ohio State University Comprehensive Cancer Center in Columbus.

Much attention has been focused on the addition of bevacizumab (Avastin) to platinum-based chemotherapy in the treatment of advanced NSCLC because the combination has been shown to improve objective response rates, progression-free survival, and overall survival in this population, Dr. Otterson explained. However, bevacizumab’s association with hemorrhagic complications precludes its indication for patients already at increased risk of bleeding, including those with squamous cell carcinoma or a history of hemoptysis, as well as those taking anticoagulant medication,

For these patients, paclitaxel – a compound that stabilizes microtubules to induce cell death – plus the DNA-targeting platinum compound carboplatin is a common therapeutic option, but it is frequently associated with hypersensitivity reactions to the toxic solvent Cremophor through which paclitaxel is delivered. In contrast, nab-paclitaxel (Abraxane) is a solvent-free formulation delivered by a nanoparticle technology that binds to the natural protein albumin.

"It is thought that delivering paclitaxel with this technology causes fewer hypersensitivity reactions and may lead to greater drug uptake in tumors," Dr. Otterson said, noting that "higher doses can be administered over a shorter infusion time without the need for special infusion sets or premedications."

A previous randomized controlled trial comparing the nab-paclitaxel plus carboplatin combination with the conventional paclitaxel plus carboplatin combination in advanced NSCLC patients demonstrated superior overall response rates with the former combination, especially in patients with squamous cell histology, Dr. Otterson said. Based on this finding, the current study is focusing specifically on squamous cell patients and others whose bleeding risk precludes bevacizumab treatment, he said.

The investigators enrolled 63 chemotherapy-naive NSCLC patients (21 female and 42 male) in the trial, including 48 with squamous cell carcinoma, 9 with adenocarcinomas, 4 with NSCLC not otherwise specified, and 2 with adenosquamous carcinoma, Dr. Otterson said. Of the patients with nonsquamous disease, 11 had a history of hemoptysis and 2 had a history of thrombosis, while one patient was undergoing therapeutic anticoagulation. The average tobacco use history for all of the patients, median age 63 years, was 50-pack years, he said.

At baseline, microRNA profiles were generated from blood/serum samples acquired from all of the patients. Treatment was administered every 21 days, initially at 300 mg per m²/AUC=6, then adjusted to 260 mg per m²/AUC=6 because of excess neuropathy, Dr. Otterson said. The study’s primary end point is overall response rate: safety and toxicities as well as overall survival and progression-free survival are secondary end points.

Preliminary findings for 53 patients evaluable to date indicate that 22 patients experienced a partial response to the therapy, while none experienced a complete response, for an ORR of 41.5%. The investigators observed stable disease in 21 patients, and progressive disease in 10 patients, Dr. Otterson said.

With respect to tolerability, "more than 10% of the patients experienced grade 3/4 toxicities," including hematologic toxicity in 36 patients febrile neutropenia in 9, infection in 15, sensory neuropathy in 17, dyspnea in 10, and dehydration in 8. Additionally, there were four deaths, reported as grade 5 toxicities, including sudden death in one patient and respiratory failure in another, he said.

Although median overall survival and progression-free survival, at 9.7 months and 5 months, respectively, "were not as high as we would have liked to see," the apparent durability of the treatment – some of the patients did not require additional treatment for at least 6 months – is "surprising and promising," Dr. Otterson said: "Based on the findings, additional investigation in the squamous cell population, in particular, is warranted."

The study was supported by Abraxis Biosciences. Dr. Otterson reported having no relevant conflicts of interest.

CHICAGO – Combination therapy with nanoparticle albumin bound–paclitaxel and carboplatin may be an option for the subset of advanced non–small cell lung cancer patients who are ineligible for bevacizumab treatment because of bleeding risk.

The combined treatment produced an objective response rate of more than 40% among non–small cell lung cancer (NSCLC) patients with squamous histology or other hemorrhagic risk factors in a single-arm, single institution, phase II trial presented at the annual meeting of the American Association for Cancer Research.

The preliminary results, which include evidence of "tolerable toxicity," are especially encouraging because of the limited treatment options available to this patient population, according to the senior investigator Dr. Gregory Otterson of the Ohio State University Comprehensive Cancer Center in Columbus.

Much attention has been focused on the addition of bevacizumab (Avastin) to platinum-based chemotherapy in the treatment of advanced NSCLC because the combination has been shown to improve objective response rates, progression-free survival, and overall survival in this population, Dr. Otterson explained. However, bevacizumab’s association with hemorrhagic complications precludes its indication for patients already at increased risk of bleeding, including those with squamous cell carcinoma or a history of hemoptysis, as well as those taking anticoagulant medication,

For these patients, paclitaxel – a compound that stabilizes microtubules to induce cell death – plus the DNA-targeting platinum compound carboplatin is a common therapeutic option, but it is frequently associated with hypersensitivity reactions to the toxic solvent Cremophor through which paclitaxel is delivered. In contrast, nab-paclitaxel (Abraxane) is a solvent-free formulation delivered by a nanoparticle technology that binds to the natural protein albumin.

"It is thought that delivering paclitaxel with this technology causes fewer hypersensitivity reactions and may lead to greater drug uptake in tumors," Dr. Otterson said, noting that "higher doses can be administered over a shorter infusion time without the need for special infusion sets or premedications."

A previous randomized controlled trial comparing the nab-paclitaxel plus carboplatin combination with the conventional paclitaxel plus carboplatin combination in advanced NSCLC patients demonstrated superior overall response rates with the former combination, especially in patients with squamous cell histology, Dr. Otterson said. Based on this finding, the current study is focusing specifically on squamous cell patients and others whose bleeding risk precludes bevacizumab treatment, he said.

The investigators enrolled 63 chemotherapy-naive NSCLC patients (21 female and 42 male) in the trial, including 48 with squamous cell carcinoma, 9 with adenocarcinomas, 4 with NSCLC not otherwise specified, and 2 with adenosquamous carcinoma, Dr. Otterson said. Of the patients with nonsquamous disease, 11 had a history of hemoptysis and 2 had a history of thrombosis, while one patient was undergoing therapeutic anticoagulation. The average tobacco use history for all of the patients, median age 63 years, was 50-pack years, he said.

At baseline, microRNA profiles were generated from blood/serum samples acquired from all of the patients. Treatment was administered every 21 days, initially at 300 mg per m²/AUC=6, then adjusted to 260 mg per m²/AUC=6 because of excess neuropathy, Dr. Otterson said. The study’s primary end point is overall response rate: safety and toxicities as well as overall survival and progression-free survival are secondary end points.

Preliminary findings for 53 patients evaluable to date indicate that 22 patients experienced a partial response to the therapy, while none experienced a complete response, for an ORR of 41.5%. The investigators observed stable disease in 21 patients, and progressive disease in 10 patients, Dr. Otterson said.

With respect to tolerability, "more than 10% of the patients experienced grade 3/4 toxicities," including hematologic toxicity in 36 patients febrile neutropenia in 9, infection in 15, sensory neuropathy in 17, dyspnea in 10, and dehydration in 8. Additionally, there were four deaths, reported as grade 5 toxicities, including sudden death in one patient and respiratory failure in another, he said.

Although median overall survival and progression-free survival, at 9.7 months and 5 months, respectively, "were not as high as we would have liked to see," the apparent durability of the treatment – some of the patients did not require additional treatment for at least 6 months – is "surprising and promising," Dr. Otterson said: "Based on the findings, additional investigation in the squamous cell population, in particular, is warranted."

The study was supported by Abraxis Biosciences. Dr. Otterson reported having no relevant conflicts of interest.

CHICAGO – Combination therapy with nanoparticle albumin bound–paclitaxel and carboplatin may be an option for the subset of advanced non–small cell lung cancer patients who are ineligible for bevacizumab treatment because of bleeding risk.

The combined treatment produced an objective response rate of more than 40% among non–small cell lung cancer (NSCLC) patients with squamous histology or other hemorrhagic risk factors in a single-arm, single institution, phase II trial presented at the annual meeting of the American Association for Cancer Research.

The preliminary results, which include evidence of "tolerable toxicity," are especially encouraging because of the limited treatment options available to this patient population, according to the senior investigator Dr. Gregory Otterson of the Ohio State University Comprehensive Cancer Center in Columbus.

Much attention has been focused on the addition of bevacizumab (Avastin) to platinum-based chemotherapy in the treatment of advanced NSCLC because the combination has been shown to improve objective response rates, progression-free survival, and overall survival in this population, Dr. Otterson explained. However, bevacizumab’s association with hemorrhagic complications precludes its indication for patients already at increased risk of bleeding, including those with squamous cell carcinoma or a history of hemoptysis, as well as those taking anticoagulant medication,

For these patients, paclitaxel – a compound that stabilizes microtubules to induce cell death – plus the DNA-targeting platinum compound carboplatin is a common therapeutic option, but it is frequently associated with hypersensitivity reactions to the toxic solvent Cremophor through which paclitaxel is delivered. In contrast, nab-paclitaxel (Abraxane) is a solvent-free formulation delivered by a nanoparticle technology that binds to the natural protein albumin.

"It is thought that delivering paclitaxel with this technology causes fewer hypersensitivity reactions and may lead to greater drug uptake in tumors," Dr. Otterson said, noting that "higher doses can be administered over a shorter infusion time without the need for special infusion sets or premedications."

A previous randomized controlled trial comparing the nab-paclitaxel plus carboplatin combination with the conventional paclitaxel plus carboplatin combination in advanced NSCLC patients demonstrated superior overall response rates with the former combination, especially in patients with squamous cell histology, Dr. Otterson said. Based on this finding, the current study is focusing specifically on squamous cell patients and others whose bleeding risk precludes bevacizumab treatment, he said.

The investigators enrolled 63 chemotherapy-naive NSCLC patients (21 female and 42 male) in the trial, including 48 with squamous cell carcinoma, 9 with adenocarcinomas, 4 with NSCLC not otherwise specified, and 2 with adenosquamous carcinoma, Dr. Otterson said. Of the patients with nonsquamous disease, 11 had a history of hemoptysis and 2 had a history of thrombosis, while one patient was undergoing therapeutic anticoagulation. The average tobacco use history for all of the patients, median age 63 years, was 50-pack years, he said.

At baseline, microRNA profiles were generated from blood/serum samples acquired from all of the patients. Treatment was administered every 21 days, initially at 300 mg per m²/AUC=6, then adjusted to 260 mg per m²/AUC=6 because of excess neuropathy, Dr. Otterson said. The study’s primary end point is overall response rate: safety and toxicities as well as overall survival and progression-free survival are secondary end points.

Preliminary findings for 53 patients evaluable to date indicate that 22 patients experienced a partial response to the therapy, while none experienced a complete response, for an ORR of 41.5%. The investigators observed stable disease in 21 patients, and progressive disease in 10 patients, Dr. Otterson said.

With respect to tolerability, "more than 10% of the patients experienced grade 3/4 toxicities," including hematologic toxicity in 36 patients febrile neutropenia in 9, infection in 15, sensory neuropathy in 17, dyspnea in 10, and dehydration in 8. Additionally, there were four deaths, reported as grade 5 toxicities, including sudden death in one patient and respiratory failure in another, he said.

Although median overall survival and progression-free survival, at 9.7 months and 5 months, respectively, "were not as high as we would have liked to see," the apparent durability of the treatment – some of the patients did not require additional treatment for at least 6 months – is "surprising and promising," Dr. Otterson said: "Based on the findings, additional investigation in the squamous cell population, in particular, is warranted."

The study was supported by Abraxis Biosciences. Dr. Otterson reported having no relevant conflicts of interest.