Functional Profiling to Select Chemotherapy in Advanced or Metastatic NSCLC

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Functional profiling using EVA/PCD doubles response rate and improves survival in NSCLC patients

Functional profiling using ex-vivo analysis of programmed cell death (EVA/PCD) doubles the response rate and improves time-to-progression and survival in patients with advanced lung cancer, according to a Phase II clinical trial conducted by investigators at Rational Therapeutics and the MemorialCare Todd Cancer Institute (Long Beach, CA) and published in the October issue of Anticancer Research.

"Medical oncologists have long pursued methods that can match patients to available therapies," said Dr. Robert Nagourney, lead investigator. "This study confirms the ability of a laboratory test to accurately predict drug activity for individual patients."

Functional profiling provides a window into the dynamic process by which human tumor cells respond to therapy. By capturing cells within their natural microenvironment, human biology is recreated in the laboratory.

The article, titled "Functional Profiling to Select Chemotherapy in Untreated, Advanced or Metastatic Non-Small Cell Lung Cancer," describes results achieved in patients who received first-line chemotherapy based on their individual ex-vivo analysis.

Using only FDA-approved, standard lung cancer drugs available to all oncologists, this process of laboratory selection provided a 64.5 percent response rate - more than double the national average of 30 percent (p = 0.00015), well established in the literature. More importantly, the median overall survival of 21.3 months was nearly two-fold longer than the best results of 13.5 months reported for non-assay based standard treatments. Strikingly, among the Stage IV (metastatic) patients, there are several who remain alive approaching eight years since diagnosis.

"These results suggest that laboratory selection of chemotherapy can change the natural history of this lethal disease," said Dr. Nagourney. "What makes the EVA/PCD approach unique is its capacity to capture human tissues in their native state, recreating conditions found in the human body."

Attempts to use gene profiling in this disease resulted in failure and controversy ("How Bright Promise In Cancer Testing Fell Apart." - Gina Kolata, New York Times, July 7, 2011). Contrary to gene-based methods, functional platforms capture the systems biology of human tumors in real-time providing therapeutic insights that translate directly into improved clinical outcomes.

Source: Rational Therapeutics

http://www.youtube.com/watch?v=BKh-rMCc4dQ&feature=youtu.be

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Functional Profiling to Select Chemotherapy in Advanced NSCLC

Functional Profiling to Select Chemotherapy in Untreated, Advanced or Metastatic Non-Small Cell Lung Cancer

Robert A. Nagourney 1,2, Jonathan B. Blitzer 1, Robert L. Shuman 1, Thomas J. Asciuto 1, Eknath A. Deo 1, Marylyn Paulsen 1, Robert L. Newcomb 3, Steve S. Evans 2

1. Memorial Medical Center of Long Beach, Todd Cancer Institute, Long Beach, CA
2. Rational Therapeutics, Long Beach, CA
3. Institute for Clinical & Translational Science, University of California, Irvine, CA

Abtract

Background Aim:

To assess the impact of drug selection upon the treatment of advanced and metastatic non-small cell lung cancer (NSCLC), we applied a functional platform that measures drug induced cell death in human tumor primary-culture micro-spheroids isolated from surgical specimens.

Patients and Methods:

At diagnosis, microspheroids isolated by mechanical and enzymatic disaggregation were examined for drug-induced cell-death by morphology and staining characteristics. Drugs were administered using standard protocols. Thirty-one patients, who received at least one cycle of therapy, were evaluable. All patients signed informed consent.

Results:

Twenty of 31 patients responded (64.5%). 1 completely and 19 partially, providing a two-fold improvement over historical control of 30% (p=0.00015), a median time to progression of 8.5 months and a median overall survival of 21.3 months.

Conclusion:

This functional platform is feasible and provides a favorable objective response rate, time to progression and survival in advanced, metastatic, untreated NSCLC, and warrants further evaluation.

Source: Anticaner Research October 2012 vol. 32 no. 10; 4454-4460

http://ar.iiarjournals.org/content/32/10/4453.abstract?sid=eb8c3504-bee5-4756-a1a8-1ae7c0d554dc

http://www.rationaltherapeutics.com/downloads/pdfs/EVAPCD.pdf

Using only FDA-approved, standard lung cancer drugs available to all oncologists, this process of laboratory selection provided a 64.5 percent response rate – more than double the national average of 30 percent (p = 0.00015), well established in the literature. More importantly, the median overall survival of 21.3 months was nearly two-fold longer than the best results of 13.5 months reported for non-assay based standard treatments. Strikingly, among the Stage IV (metastatic) patients, there are several who remain alive approaching eight years since diagnosis.

Standard treatment protocols, administered in accordance with published results in thoracic oncology literature, included: Carboplatin & Paclitaxel (Taxol); Cisplatin & Navelbine (vinorelbine); Cisplatin & Gemzar (gemcitabine); Carboplatin & Gemzar; Carboplatin & Alimta (pemetrexed); Tarceva (erlotinib); Tarceva & Avastin (bevacizumab); Carboplatin & Taxol & Avastin; Cisplatin & Navelbine & Avastin; Taxol; Docetaxel (Taxotere); Navelbine; Taxotere & Gemzar; Campto (Irinotecan); Campto & Cisplatin.

To date, they are tracking a 100% response rate to Tarceva in the select populations; even patients who have not been found to carry recognized mutations.

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Functional Profiling to Select Chemotherapy in Advanced NSCLC

Functional Profiling to Select Chemotherapy in Untreated, Advanced or Metastatic Non-Small Cell Lung Cancer

Robert A. Nagourney 1,2, Jonathan B. Blitzer 1, Robert L. Shuman 1, Thomas J. Asciuto 1, Eknath A. Deo 1, Marylyn Paulsen 1, Robert L. Newcomb 3, Steve S. Evans 2

1. Memorial Medical Center of Long Beach, Todd Cancer Institute, Long Beach, CA
2. Rational Therapeutics, Long Beach, CA
3. Institute for Clinical & Translational Science, University of California, Irvine, CA

Abtract

Background Aim:

To assess the impact of drug selection upon the treatment of advanced and metastatic non-small cell lung cancer (NSCLC), we applied a functional platform that measures drug induced cell death in human tumor primary-culture micro-spheroids isolated from surgical specimens.

Patients and Methods:

At diagnosis, microspheroids isolated by mechanical and enzymatic disaggregation were examined for drug-induced cell-death by morphology and staining characteristics. Drugs were administered using standard protocols. Thirty-one patients, who received at least one cycle of therapy, were evaluable. All patients signed informed consent.

Results:

Twenty of 31 patients responded (64.5%). 1 completely and 19 partially, providing a two-fold improvement over historical control of 30% (p=0.00015), a median time to progression of 8.5 months and a median overall survival of 21.3 months.

Conclusion:

This functional platform is feasible and provides a favorable objective response rate, time to progression and survival in advanced, metastatic, untreated NSCLC, and warrants further evaluation.

Source: Anticaner Research October 2012 vol. 32 no. 10; 4454-4460

http://ar.iiarjournals.org/content/32/10/4453.abstract?sid=eb8c3504-bee5-4756-a1a8-1ae7c0d554dc

http://www.rationaltherapeutics.com/downloads/pdfs/EVAPCD.pdf

Using only FDA-approved, standard lung cancer drugs available to all oncologists, this process of laboratory selection provided a 64.5 percent response rate – more than double the national average of 30 percent (p = 0.00015), well established in the literature. More importantly, the median overall survival of 21.3 months was nearly two-fold longer than the best results of 13.5 months reported for non-assay based standard treatments. Strikingly, among the Stage IV (metastatic) patients, there are several who remain alive approaching eight years since diagnosis.

Standard treatment protocols, administered in accordance with published results in thoracic oncology literature, included: Carboplatin & Paclitaxel (Taxol); Cisplatin & Navelbine (vinorelbine); Cisplatin & Gemzar (gemcitabine); Carboplatin & Gemzar; Carboplatin & Alimta (pemetrexed); Tarceva (erlotinib); Tarceva & Avastin (bevacizumab); Carboplatin & Taxol & Avastin; Cisplatin & Navelbine & Avastin; Taxol; Docetaxel (Taxotere); Navelbine; Taxotere & Gemzar; Campto (Irinotecan); Campto & Cisplatin.

To date, they are tracking a 100% response rate to Tarceva in the select populations; even patients who have not been found to carry recognized mutations.

Incorporating Avastin and Tarceva in Combined-Modality Treatment

The November 10, 2012 issue of the Journal of Clinical Oncology published a highly instructive report on the incorporation of Avastin (bevacizumab) and Tarceva (erlotinib) into the treatment of Stage III NSCLC in combination with radiation for the treatment.

The article regarded a pilot study that incorporated an anti-VEGF antibody Avastin (bevacizumab) with EGFR TKI Tarceva (erlotinib) along with chemotherapy and radiation. In this trial the objective response rate of 39 percent, median progression-free survival of 10.2 months and median overall survival of 10.4 months, were not demonstrably superior to contemporary results, yet toxicity was significantly enhanced.

The investigators recommended against further exploration of this combination. Here the aggressive integration of targeted and conventional therapies proved a misadventure.

According to Dr. Robert A. Nagourney of Rational Therapeutics, the trial represented clinicians’ desire to engage in theoretically attractive clinical trials only to find that they reflect ineffective and/or more toxic treatment regimens. This lung cancer experience reflects the failure of the research community to dedicate adequate resources to predictive clinical models.

Combinations of chemotherapy with target therapies have been the subject of investigation at Rational Therapeutics in Long Beach, California for more than a decade. For example, they observed antagonism between platins and the EGFR antagonists Iressa (gefitinib) and Tarceva (erlotinib) two years before publication of the unsuccessful INTACT I and II Trials and three years before the unsuccessful TALENT and TRIBUTE trials.

All four of these trials combined platin based doublets with EGF-TKI’s. More recently Rational Therapeutics successfully identified favorable interactions between Tarceva (erlotinib) and VEGF inhibitors in individual patients that have provided durable responses in their NSCLC patients as first line therapy, now out to four and five years since diagnosis. 

These experiences represent opportunities to explore novel therapies and avoid inadvertent antagonisms and misadventures. In the recent JCO, a good treatment was missed while a bad treatment was advanced.

Functional profiling through use of the EVA-PCD assay may represent the critical path from bench to bedside that the deputy director of the Center for Drug Evaluation and Research at the Food and Drug Administration, Janet Woodcock has described as a crying need.

Incorporating Bevacizumab and Erlotinib in the Combined-Modality Treatment of Stage III Non–Small-Cell Lung Cancer: Results of a Phase I/II Trial

http://jco.ascopubs.org/content/30/32/3953.abstract