Functional Profiling to Select Chemotherapy in Advanced or Metastatic NSCLC

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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.

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