November is Lung Cancer Awareness Month

With November designated as Lung Cancer awareness month we have the opportunity to focus national attention on this disease, the leading cause of cancer death in America.

It may come as a surprise to many that lung cancer causes more deaths than prostate, breast and colorectal cancer combined. Lung cancer is the big kahuna. And up until the last several years, no one seemed to be paying much attention. It may be that people considered lung cancer a disease associated with cigarette smoking and therefore, in some way, the individual victim’s fault. However, we are now witness to a changing biology wherein the predominant histology of lung cancer, previously squamous cell, has transitioned to adenocarcinoma.

While the incidence in males has fallen, the incidence in females has risen. Strikingly, the incidence of lung cancer in non-smokers is rapidly climbing. Indeed, up to 20 percent of lung cancers today do not appear to be directly related to cigarettes or known exposures at all.

Our recent publication of a clinical trial in lung cancer patients was highly instructive. First, we were able to double the response rate and nearly double the survival through functional profiling (EVA-PCD®).

Second, there was no “right” treatment for patients. Different treatment combinations worked best for each patient with no single combination working for all.

Third, many patients did well with first line targeted agents. In fact, several long-term survivors have never received any form of cytotoxic chemotherapy, despite widely metastatic disease at presentation.

Several questions remain. Among them, the role of the repeat biopsies in patients with recurrent disease.  Several patients under my care have undergone additional biopsies each time a recurrence was documented with the new assay findings guiding us to a different treatment regimen. It is not impossible to imagine a day when cancer treatments will be modified and changed the way contemporary internists switch antihypertensives or cholesterol lowering drugs. That is, lung cancer like these maladies is becoming a chronic disease.

With several patients out over five years this strategy has served us well in select cases. A second issue surrounds the early introduction of experimental agents. Should we not have the opportunity to utilize drugs that have succeeded in Phase I trials, (and are thereby known to be safe for human administration), for patients whose cancer tissue reveals a favorable profile ex-vivo? I, for one, would relish the opportunity to administer second-generation EGFr-TKIs to c-MET inhibitors, to appropriately selected candidates. Smart drugs need smart mechanisms to get to market.

With the advent of lung cancer awareness month we have the opportunity to educate the public and expand awareness of the desperate need for advances in this disease. The disparity in funding for lung cancer patients compared with ovarian or breast cancer patients is disturbing. For every lung cancer death, there are five to 10 times more dollars expended on research to prevent breast and ovarian cancer deaths. While we applaud the successes in breast and ovarian cancer treatment we encourage lung cancer patients to call your congressperson to make lung cancer a front burner issue.

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One of our most gratifying success stories is Pat Merwin, now four years since diagnosis. Pat has organized a local (Long Beach, CA) observance of the national lung cancer awareness vigil to be held on Tuesday, November 13. I could not be happier than to be the invited speaker for this important occasion and to be with many of my patients.

Gee (G719X) Whiz: Novel Mutations and Response to Targeted Therapies

In a recent online forum a patient described her experience using Tarceva as a therapy for an EGFR mutation negative lung cancer. For those of you familiar with the literature you will know that Lynch and Paez both described the sensitizing mutations that allow patients with certain adenocarcinoma to respond beautifully to the small molecule inhibitors.  The majority of these mutations are found in Exon 19 and Exon 21, within the EGFR domain. Response rates for the EGFR-TKI (gefitinib and erlotinib) clearly favor mutation positive patients. Depending upon the study, mutation positive patients have response rates from 53 – 100 percent, generally around 70 percent, while mutation negative response patients have a response rate of 0 – 25 percent, generally about 10 percent.So why don’t all the mutation positive patients respond and conversely why do some mutation negative patients respond?

The story outlined in this online forum gives some insight. The individual in question carried a rare, and only recently recognized, Exon 18 mutation known as a G719X. This uncommon form of mutation had previously been unknown and few laboratories knew to test for it. Nonetheless, G719X positive patients respond to erlotinib and related agents. Indeed, there may be reason to believe that the more potent irreversible EGFR/HER2 dual inhibitor HKI-272, may be even more selective for this point mutation.

The excellent and durable response described by this individual, would not have been possible had the patient’s first physician followed the rules. That is, had her physician refused to give erlotinib to an (putatively) EGFR mutation negative patient she might well not be here to tell her story. More to the point, her good response (a clinical observation) led to the next level of investigation, namely the identification of this specific EGFR variant

The lessons from this experience are numerous. The first is that cancer biology is complex and, to paraphrase E.O. Wilson, was not put on earth for us to necessarily figure it out. The second, is that molecular biologists can only seek and identify that which they know about apriori.  To wit, if you don’t know about it (G719X) and you don’t have a test for it, and you don’t know to look for it, then it’s a virtual certainty that you aren’t going to find it.

The premise of our work at Rational Therapeutics is that the observation of a biological signal identifies a candidate for therapy whether we understand or recognize the target. Crizotinib was originally developed as a clinical therapy for patients who carried the CMET mutation. Serendipity led to the recognition that the responding subpopulation was actually carrying a heretofore-unrecognized ALK gene rearrangement. Sorafenib was originally evaluated for the treatment of BRAF mutation positive diseases. Yet it was the drug’s cross-reactivity with the VGEF tyrosine kinases that lead to its broad clinical applications. Each of these phenomena represents accidental successes. Were it not for the clinical observation of response in patients, the investigators conducting these trials would have been unlikely to make the discoveries that today provide such good clinical responses in others.

To put it quite simply, these patients and their disease entities educated the molecular biologists.

When we first identified lung cancer as a target for gefitinib, and began to administer the closely related erlotinib to lung cancer patients, neither Lynch nor Paez had identified the sensitizing EGFR mutations. That had absolutely no impact upon the excellent responses that we observed. It didn’t matter why it worked, but that it worked.  While the EGFR story has now been well-described, might we not use functional analytical platforms (functional profiling) to gain insights into the next, and the next generation of drugs and therapies that target pathways like MEK, ERK, SHH, FGFR, PI3K, etc., etc., etc. . . .

Time for Rational Therapy?

At the 2012 American Association for Cancer Research (AACR) meeting recently held in Chicago, I again observed that the AACR presentations continue to diverge from those at the American Society of Clinical Oncology (ASCO). At this year’s meeting, I’m not sure I heard the word “chemotherapy” a single time. That is, all of the alphabet soup combinations that make up the sessions at ASCO are nowhere to be found at the AACR meeting. Instead, targeted agents, genomics, proteomics and the growing field of metabolomics reign supreme.

Over the coming weeks, I will blog about some of the more interesting presentations I attended. However, I note below several themes that seemed to emerge.

First: That cancer patients are highly unique. In one presentation using phosphoprotein signatures to connect genetic features to phenotypic expression, the investigator conducted 21 phosphoprotein signatures and found 21 different patterns. This, he noted, reflected the “uniqueness” of each individual.

Additional themes included the growing development of meaningfully effective immune therapies. There was evidence of a renewed interest in tissue cultures as the best platform to study drug effects and interactions. Although virtually every presentation began with the obligatory reference to genomic analysis, almost every one of them then doubled back to metabolism as the principal driver of human cancer.

Interestingly, the one phrase that cropped up time and time again was rational therapeutics. Although they did not appear to be referring to our group, it was comforting to note that they are at least, finally coming around to our philosophy.

The Future – EVA-PCD® Platform and Targeted Agents

As I mentioned in my last post, in our presentation at the 2010 ASCO Annual Meeting, we showed clinical response rates were doubled by using the Ex-Vivo Analysis of Programmed Cell Death (EVA-PCD®) platform with standard FDA approved chemotherapeutic agents in NSCLC patients.

If we can achieve these types of results by simply reconfiguring existing drugs, it suggests that the EVA-PCD platform could provide even better results as we introduce larger numbers of active, targeted agents.

One such agent, PF-1066 provided an overall response rate of 64 percent when patients were selected for the EML4-ALK fusion oncogene. This type of approach, the selection of candidates for therapy predicated upon the biology of the patient, is precisely the premise underlying all of our work. While the PF-1066 data was strongly positive, it represented a very select population of lung cancer patients who carry a specific gene profile. Of all NSCLC patients, only 3-4 percent carry this gene. While recognizing targets like EGFR and ALK continue to improve responses, the EVA-PCD platform is capable of identifying patients for response even when the specific underlying genetic mechanism may be less well characterized. The capacity of the EVA-PCD platform to measure global cellular response enables us to select candidates for whom no known genetic predisposition exists.

New Drugs Are Not Always Better Drugs

The most common form of renal carcinoma is the clear cell variant. These tumors are driven by mutations in the VHL gene and are associated with hyper-vascularity. Understanding the pathogenesis of this disease has enabled researchers to develop new classes of drugs that target VEGF, both at the protein level (Bevacizumab) and at the tyrosine kinase level (sorafenib, sunitinib, etc.). An additional class of drugs targets the intracellular metabolic pathway known as mTOR. Patients newly diagnosed with renal cell carcinoma of the clear cell type are treated with drugs that target these pathways. However, responses occur in the minority of patients. It is unclear why some patients respond to these interventions while others fail.

The EVA-PCD™ analysis is equally applicable to classic cytotoxic drugs and the newer classes of targeted agents, which include Sunitinib and Sorafenib and the rapalogs like Everolimus and Temsirolimus. This enables our lab to explore whether renal cell carcinoma patients are likely to respond to vascular or mTOR targeting classes of drugs. Interestingly, patients who do not respond to these classes of drugs may nonetheless have sensitivity to cytotoxic chemotherapeutic agents. One example currently undergoing therapy is a 51 year old male who was presented in February 2009 with widely metastatic renal cell carcinoma, and a destructive lesion of the right femur requiring open surgical stabilization. Tissue removed from the patient’s femur at the time of the orthopedic surgery was submitted for an EVA-PCD™ analysis. The results were highly instructive, indicating clear resistance to the VEGF targeting agents and the rapalogs but substantial sensitivity to a novel combination of cytotoxic drugs. The patient received an opinion from a renowned renal cell expert who immediately placed him on sunitinib (Sutent™). When he failed sunitinib he was then placed upon Everolimus (Afinitor). Again the patient failed to respond. Progression of his disease was heralded by brain metastases that required both neurosurgery and cranial irradiation. He then revealed rapidly progressive pulmonary metastases as well as large painful bilateral axillary lymphadenopathy and large painful subcutaneous lesions. In light of the patient’s failure of targeted agents, he was treated with a three-drug combination identified to be active in the EVA-PCD™ analysis. The response to date has been dramatic, with complete resolution of subcutaneous lesions and lymph nodes , and objective improvement in the pulmonary metastases by CT scan. The patient remains on therapy, with continued excellent response.

This is but one example of an unexpectedly good response to classic cytotoxic drugs following a failure to respond to the newest classes of targeted agents. These experiences reinforce the need for cancer therapies to be individualized. They also remind us, as physicians, that it is the good outcome of the patient not the therapy applied that constitute successful application of the healing arts.

When to Use Assay Testing

There is a common misconception that chemosensitivity-resistance assays are only useful for patients in the relapsed state once they have failed conventional first line therapy. This assertion is wrong on several levels.

  1. First, the best outcomes in cancer medicine are known to occur with first line therapies. The selection of the most active, least toxic drug or combination should be the goal of every physician at the time of initial therapy. As CSRAs have well established performance characteristics (sensitivity and specificity), their positive predictive accuracy (the likelihood that a patient with a sensitive assay will respond to the clinical treatments selected) are highest when they are applied in the first line setting.
  2. Secondly, on theoretical grounds, exposure to randomly selected chemotherapeutics, many of which are mutagens, may select for or induce drug resistance, diminishing the likelihood of a good outcome in second line or subsequent therapy.
  3. Finally, the introduction of active targeted agents provides patients the opportunity to receive first line therapies that do not carry the side effects and toxicities of classic cytotoxic chemotherapies. Our experience with first line Erlotinib in non-small cell lung cancer today provides response rates that exceed those associated with patients selected based on EGFr mutation or overexpression. Furthermore, the selection of candidates for combined targeted agents, e.g. EGFR & VEGF inhibitors, etc. provides a growing opportunity to introduce novel combinations into the first line setting. The growing cost and potential toxicity of some of these agents make the application of accurate selective methodologies increasingly crucial.

First line chemotherapy provides patients their best opportunity for a good outcome. There is no rationale for exposing patients to randomly selected toxic and potentially ineffective therapy when clinically validated selective methodologies can be applied in the first line as well as second line setting and beyond.

The Clinical Applications of Functional Profiling CSRA: Lung Cancer

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 percent and median survivals of 12 months remain static over decades. The five-year survival of 15 percent 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 percent to 41 percent 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 percent 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 percent, 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.