Functional profiling stage IV NSCLC: phase II trial

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Functional profiling using EVA/PCD for prescribing treatment regimens for Stage IV NSCLC improve survival

Metastatic NSCLC Survival Doubled Using Functional Profiling to Select Drug Treatments

June 4, 2010

A team of investigators at Rational Therapeutics, Inc. and the Malcolm Todd Cancer Institute (Long Beach, Calif.) has reported that functional profiling using ex-vivo analysis of programmed cell death (EVA/PCD) can be used to prescribe treatment regimens that double the response rate and survival in patients with Stage IV non-small cell lung cancer (NSCLC). The findings of their phase II clinical trial were presented on Sunday, June 6th at the 46th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.

Functional profiling provides a real-time window on how human tumors will respond to therapy. By capturing cells within their natural microenvironment, it approximates human biology in the laboratory. NSCLC - the leading cause of cancer death in the US, with little change in survival for decades - offers an ideal target for this approach.

The ASCO study presentation titled, "Phase II Trial of Personalized Chemotherapy In Stage IV NSCLC: Clinical Application Of Functional Profiling In First-Line Therapy" (Abstract No. 7617; Citation: J. Clin Oncol 28:7s, 2010), described results achieved in patients who received first-line therapy based on their individual ex vivo analyses.

"This method for treating NSCLC allows doctors to optimize the use of existing chemotherapeutics and explore novel therapies in a way that can change the natural history of the disease," said Dr. Robert Nagourney, medical director at Rational Therapeutics. "What makes the EVA/PCD approach unique is its capacity to capture human tissues in their native state, recapitulating cellular conditions found in the human body."

While the study used only FDA-approved NSCLC drugs, it resulted in a 62 percent response rate - more than double.

"While most cancer researchers explore genomic and proteomic platforms in an effort to 'individualize' treatment, such techniques cannot approach the capacity of functional analyses to examine the complexities and redundancies of human tumor signaling pathways," added Dr. Nagourney. "Yet, it is these cellular signaling pathways that determine clinical response. Experts must be willing to accept that genotype doesn't equal phenotype."

The study prescribed treatments selected among established NSCLC drugs including Gemcitabine, Pemetrexed (Eli Lilly), Paclitaxel, Carboplatin (Bristol Myers), Vinorelbine (Roche) and Erlotinib (Genentech).

While these are the same agents already used widely by oncologists, Dr. Nagourney concluded, "It's not the drugs per se, but rather how they were selected, that changed the outcomes so dramatically. While everyone is talking about 'personalized' cancer treatment, we're doing it."

Source: Rational Therapeutics

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Phase II trial of peresonalized chemotherapy in stage IV NSCLC: Clinical application of functional profiling in first-line therapy

Sub-category: Metastatic

Category: Lung Cancer - Metastatic

Meeting: 2010 ASCO Annual Meeting

Citation: J Clin Oncol 28:7s, 2010 (suppl; abstr 7617)

Abstract No: 7617

Author(s): R. A. Nagourney, J. B. Blitzer, E. A. Deo, R. Nandan, R. Shuman, T. Asciuto, D. Mc Connell, M. Paulsen, S. S. Evans; Rational Therapeutics, Long Beach, CA; Oncology Hematology Consultants, Long Beach, CA; Malcolm Todd Cancer Institute, Long Beach, CA

Abstract:

Background

Personalized chemotherapy is an important advance for NSCLC pts. While genomic platforms have identified prognostic and predictive factors e.g., ERCC1 and RRM1/2, proteomic platforms are now identifying novel phosphoprotein targets. To address the complexity and redundancy of cell-death pathways, we applied Ex Vivo Analysis of Programmed Cell Death (EVA/PCD) (Nagourney, R. Curr Treat Opt Oncol. 2006) to select therapy for chemo-naïve pts with stage IV NSCLC.

Methods

Using morphologic and metabolic endpoints EVA/PCD gauges cellular response to drugs and signal transduction inhibitors in human tumor micro-spheroids isolated from surgical biopsies. Modified Z-scores and synergy analyses (median-effect) then select ex vivo best regimens (EVBR) from FDA-approved NSCLC drugs. Trial powered to improve ORR by 2-fold and median TTP by 50% (p=.05). All pts sign informed consent.

Results

26/32 (81%) pts are evaluable with CR = 3/26 (11.5%); PR = 15/26 (57.6%); SD = 6/26 (23%) and PD = 2/26 (7.6%) for an ORR = 18/26 (69%) and CBR = 24/26 (92.3%). Selected EVBR were CDDP/gemcitabine 12/26 (46%); CDDP/taxane 7/26 (27%); erlotinib 5/26 (19%); CDDP/vinorelbine 1/26 (4%); CDDP/pemetrexed1/25 (4%). Nine of 26 (36.6%) pts were converted to surgical/radiation candidates. All first-line erlotinib pts responded (100%).

Conclusions

At ORR = 69%, the trial has met response criteria and with current TTP up to 46 months and OS up to 60 months, accrual will be completed to allow formal TTP and OS analyses. The EVA/PCD platform, by examining drug-induced events in native-state micro-spheroids, has shown the unique capacity to capture stromal, vascular and inflammatory cell interactions with tumor cells, known crucial for clinical response prediction. Results support applications of personalized NSCLC therapy and warrant further evaluation. Supported by Memorial Medical Center Foundation, Long Beach.

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There are any number of variables that affect drugs. These include the rate of excretion of the drugs by the kidneys and liver, protein binding and a myriad of other biological factors.

Some anticancer drugs are actually pro-drugs: they need to be first activated in the liver before becoming biologically active. So in vitro testing must administer the active forms of these agents, not the pro-drug form that is given to patients.

In the body, these cells interact with and supported by other living cells, both malignant and non-malignant cells. That is why cell-death functional profiling assays study cancer cells in small clusters, or microspheroids.

Analysis of these microspheroids provides a snapshot of cancer's behavior within the human body and provides a more accurate representation of how cancer cells are likely to respond to treatment in the clinic.

It is crucial that there is no manipulation of isolated cancer cells to make them grow, which was an important point of distinction with earlier cell-growth assays.

Drs. Larry Weisenthal and Robert Nagourney adopted this concept and began applying the term microclusters.

Real-life cancers grow as a complex organism that includes both malignant and non-malignant components. It may include fibrous tissue, mesothelial cells, fibroblasts, endothelial cells, etc.

In order to exhibit its most characteristic behavior patterns, a cancer cell needs to be surrounded by a colony of other cells, both normal and malignant.

Human tumors represent micro-ecosystems composed of transformed cells, stroma, fibroblasts, vascular elements, extra-cellular protein matrices and inflammatory elements.

The behavior of human cancers and their reponse to therapy reflect the complex interplay between humoral, vascular, adhesion and cytokine-mediated events acting in concert.

Tumors are very complex organisms. Ignoring this complexity, most studies of human cancer in culture have focused upon individual tumor cells that have been removed from their complex microenvironoment.

Cells are routinely broken up by mechanical and enzymatic means, which alters their subsequent behavior. Some previous methods of assays limited their analysis only to isolated tumor cells and failed to incorporate the crucial contribution of non-tumorous elements to the cancer phenomenon.

When allowed to grow in vitro, living cancer cells develop into these tiny micro-spheroid clusters that form a complex biosystem in which each malignant cell reacts upon its fellow colonists in subtle but important ways.

Each of these microspheres contains all the complex elements of tumor biosytems that are found in the human body and which can impact clinical reponse.

Source: Nagourney RA, Kollin CA, Sommers B, Su Y-Z, Evans SS. Functional profiling of human tumors in primary culture: a platform for drug discovery and therapy selection, AACR abstract #1546, 2008

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Lung cancer, with 215,000 new diagnoses and 162,000 deaths in the United States each year, represents the leading cause in cancer death in the US. Average response rates of 30% and median survivals of 12 months remain static over decades. The five-year survival of 15% for this disease has not changed in 50 years.

While better surgical techniques and the introduction of new drugs have improved the one-year survival from 35% to 41% in the last 20 years, this has not had a major impact on overall survival.

Few diseases offer the opportunity to meaningfully improve cancer survival like lung cancer. A 25% improvement in survival in lung cancer would be the numerical equivalent of curing breast cancers outright.

Recognizing this opportunity, we have made lung cancer a principal focus of the functional profiling platform. Our current IRB approved clinical protocol in non-small cell lung cancer applies our functional profiling platform to select from among the commercially available FDA approved compendium listed drugs, in metastatic non-small cell lung cancer.

The results of our study have been submitted to national meetings. To date, our approach has more than doubled the objective response rate to 69%, improved the time to progression, provided over one-third of our stage IV patients the capacity to undergo definitive radiation or surgery, and extended the lives of some stage IV patients to five or more years.

By exploring the first line use of the newer targeted agents, many patients are achieving durable responses without ever being exposed to classic chemotherapeutic drugs. It is our intent to make these laboratory analyses available to all newly diagnosed and relapsed lung cancer patients.

Dr. Nagourney is medical and laboratory director at Rational Therapeutics, Inc., in Long Beach, California, and an instructor of Pharmacology at the University of California, Irvine School of Medicine. He is board-certified in Internal Medicine, Medical Oncology and Hematology.

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The above Phase II clinical trial in advanced lung cancer has been submitted by Dr. Nagourney and is under review for publication.

As the field of laboratory-directed therapies has confronted resistance from investigators who call for controlled clinical trials to validate this approach, Dr. Nagourney feels it is important to continue providing prospective documentation of the efficacy and clinical utility of assay-directed therapy.

While there are many excellent retrospective analyses constituting almost 2,000 patients, directed trials that use assay selection for the upfront choice of chemotherapy are more compelling yet fewer in number.

It is with a sense of satisfaction and accomplishment that he submitted this study in which previously untreated patients with metastatic lung cancer received assay-directed therapy selected from among drugs that are FDA approved, commercially available and in wide use for this disease.

In his report, he succeeded in doubling the response rate from an historical experience of 30 percent to 64 percent and achieved strong statistical significance (p=.00015). In addition, the median survival for patients in the study of 21.3 months nearly doubled the best available results in the literature of 12.5 months.

As several of the patients remain alive close to seven years at this writing, Dr. Nagourney believes that this approach to therapy has the capacity to alter the natural history of lung cancer – the leading cause of cancer death in America.

The results of the lung cancer study, in which only conventional chemotherapeutics were used, strongly supports the belief that the functional profiling laboratory platform could offer even greater opportunities to streamline the introduction of the newest classes of targeted agents.

Dr. Nagourney's group, Rational Therapeutics, Inc., has initiated discussions with a pharmaceutical firm to implement directed studies with some of the newest signal inhibitors.

It is their hope that patients with refractory malignancies, those who may not benefit from conventional therapies, will soon be able to avail themselves of these new classes of targeted agents based upon laboratory selection, all under the auspices of IRB (Institutional Review Board) approved protocols.

It is important to remember that new drugs aren’t always better drugs.

In this context, the remarkable success of one their kidney cancer patients who had shown no response to the newest targeted VEGF inhibitors, has now achieved a complete remission using assay-directed conventional cytotoxics, represents the advantage of drug selection over the random introduction of new drugs.

It reaffirms the dictum at Rational Therapeutics that all patients should receive “whatever works best.”

World renowned Oncologists are challenging the cancer industry to recognize a Chemo-Screening test (CSRA) that takes the "guesswork" out of drug selection. One of the reasons medical oncologists dont like in vitro chemosensitivity tests is that it may be in direct competition with the randomized controlled clinical trial paradigm.

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