Genomic Profiling for Lung Cancer: the Good, the Bad and the Ugly

Genomic profiling has gained popularity in medical oncology. Using NextGen platforms, protein coding regions of human tumors known as exomes can be examined for mutations, amplifications, deletions, splice variants and SNPs. In select tumors the results can be extremely helpful. Among the best examples are adenocarcinomas of the lung where EGFr, ALK and ROS-1 mutations, deletions and/or re-arrangements identified by DNA analysis can guide the selection of “targeted agents” like Erlotinib and Crizotinib.

An article published in May 2014 issue of JAMA reported results using probes for 10 “oncogenic driver” mutations in lung cancer patients. They screened for at least one gene in 1,007 patients and all 10 genes in 733. The most common was k-ras at 25%, followed by EGFR in 17% and ALK in 8%. The incidence then fell off with other EGFr mutations in 4%, B-raf mutations in 2%, with the remaining mutations each found in less than 1%.

Median survival at 3.5 vs 2.4 years was improved for patients who received treatments guided by the findings (Kris MG et al, Using multiplex assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA, May 2014). Do these results indicate that genomic analyses should be used for treatment selection in all patients? Yes and no.

Noteworthy is the fact that 28% of the patients had driver mutations in one of three genes, EGFr, HER2 or ALK. All three of these mutations have commercially available chemotherapeutic agents in the form of Erlotinib, Afatinib and Crizotinib. Response rates of 50% or higher, with many patients enjoying durable benefits have been observed. Furthermore, patients with EGFr mutations are often younger, female and non-smokers whose tumors often respond better to both targeted and non-targeted therapies. These factors would explain in part the good survival numbers reported in the JAMA article. Today, a large number of commercial laboratories offer these tests as part of standard panels. And, like k-ras mutations in colon cancer or BCR-abl in CML (the target of Gleevec), the arguments in favor of the use of these analyses is strong.

Non-small cell lung cancer

Non-small cell lung cancer

But what of the NSCLC patients for whom no clear identifiable driver can be found? What of the 25% with k-ras mutations for whom no drug exists? What of those with complex mutational findings? And finally what of those patients whose tumors are driven by normal genes functioning abnormally? In these patients no mutations exists at all. How best do we manage these patients?

I was reminded of this question as I reviewed a genomic analysis reported to one of my colleagues. He had submitted a tissue block to an east coast commercial lab when one of his lung cancer patients relapsed. The results revealed mutations in EGFr L858R & T790M, ERBB4, HGF, JAK2, PTEN, STK11, CCNE1, CDKN2A/B, MYC, MLL2 W2006, NFKB1A, and NKX2-1. With a tumor literally bristling with potential targets, what is a clinician to do? How do we take over a dozen genetically identified targets and turn them into effective treatment strategies? In this instance, too much information can be every bit as paralyzing as too little.

Our preferred approach is to examine the small molecule inhibitors that target each of the identified aberrancies in our laboratory platform. We prefer to drill down to the next level of certainty e.g. cellular function. After all, the presence of a target does not a response make.

In this patient I would conduct a biopsy. This would enable us to examine the drugs and combinations that are active against the targets. A “hit” by the EVA-PCD assay would then isolate the “drivers” from the “passengers” and enable the clinician to intelligently select effective treatments. Combining genomic analyses with functional profiling (phenotypic analyses) provides the opportunity to turn speculative observations into actionable events.

This is the essence of Rational Therapeutics.

The Changing Landscape in Non-small Cell Lung Cancer (NSCLC)

In October 2012, we published a study of patients with metastatic NSCLC whose treatment was guided by EVA-PCD laboratory analysis. The trial selected drugs from FDA approved, compendium listed chemotherapies and every patient underwent a surgical biopsy under an IRB-approved protocol to provide tissue for analysis.

The EVA-PCD patients achieved an objective response rate of 64.5 percent (2-fold higher than national average, P < 0.0015) and median overall survival of 21.3 months (nearly 2-fold longer than the national average of 12.5 months).

Non-small cell lung cancer

Non-small cell lung cancer

The concept of conducting biopsies in patients with metastatic NSCLC was not only novel in 2004, it was downright heretical. Physicians argued forcefully that surgical procedures should not be undertaken in metastatic disease fearing risks and morbidity. Other physicians were convinced that drug selection could not possibly improve outcomes over those achieved with well-established NCCN guidelines. One oncologist went so far as to demand a formal inquiry. When the hospital was forced to convene an investigation, it was the co-investigators on the IRB approved protocol and the successfully treated patients who ultimately rebuffed this physician’s attempt to stifle our work.

With the publication of our statistically superior results and many of our patients surviving more than 5 years, we felt vindicated but remain a bit battle scarred.

I was amused when one of my study co-authors (RS) recently forwarded a paper authored at the University of California at Davis about surgical biopsies and tumor molecular profiling published by The Journal of Thoracic and Cardiovascular Surgery. This single institution study of twenty-five patients with metastatic NSCLC reported their experience-taking patients with metastatic disease to surgical biopsy for the express purpose of selecting therapy. Sixty four percent were video assisted thoracic (VATS) wedge biopsies, 16 percent pleural biopsies, 8 percent mediastinoscopies, 12 percent supraclavicular biopsies and 8 percent rib/chest wall resections. Tissues were submitted to a commercial laboratory in Los Angeles for genomic profiling.

The authors enthusiastically described their success conducting surgical procedures to procure tissue for laboratory analysis. Gone was the anxiety surrounding the risk of surgical morbidity. Gone were the concerns regarding departure from “standard” treatment. In their place were compelling arguments that recapitulated the very points that we had articulated ten years earlier in our protocol study. While the platforms may differ, the intent, purpose and surgical techniques applied for tissue procurement were exactly the same.

What the Cooke study did not describe was the response rate for patients who received “directed therapy.” Instead they provide the percent of patients with “potentially targetable” findings (76 percent) and the percent that had a “change in strategy” (56 percent) as well as those that qualified for therapeutic trials (40 percent). Though, laudable, changing strategies and qualifying for studies does not equal clinical responsiveness. One need only examine the number of people who are “potential winners” at Black Jack or those who “change their strategies” (by changing tables/dealers for example) or, for that matter, those who qualify for “high roller status” to understand the limited practical utility of these characterizations.

Nonetheless, the publication of this study from UC Davis provides a landmark in personalized NSCLC care. It is no longer possible for oncologists to decry the use of surgical biopsies for the identification of active treatments.

As none of the patients in this study signed informed consents for biopsy, we can only conclude that the most august institutions in the US now view such procedures as appropriate for the greater good of their patients. Thus, we are witness to the establishment of a new paradigm in cancer medicine. Surgical biopsies in the service of better treatment are warranted, supported and recommended. Whatever platform, functional or genomic, patient-directed therapy is the new normal and the landscape of lung cancer management has changed for the better.

The Meaning of Meaningful Improvement in Lung Cancer

When asked to define what constituted pornography in his 1964 Supreme Court decision (Jacobellis versus Ohio 1964) Justice Potter Stewart stated, “I know it when I see it.” When I reviewed an article on the changing landscape of clinical trials in non-small cell lung cancer (NSCLC) (Shifting patterns in the interpretation of phase 3 clinical trial outcomes in advanced non-small cell lung cancer: The bar is dropping, Sacher A. G. et al, J Clin Oncol May 10, 2014), Justice Stewart came to mind.

The authors selected 203 NSCLC trials from a total of 245 studies conducted between 1980 and 2010. They compared how often the studies met their endpoints with how often the study authors’ called the results “positive.” Among the findings, it seems that earlier studies (before the year 2000) were geared for overall survival, while later studies (after 2000) overwhelmingly favored progression free survival. Although patient survivals changed little, the number of trials reported as successful increased dramatically.

Non-small cell lung cancer

Non-small cell lung cancer

Progression-free survival measures how long it takes for a patient to fail treatment. That is, for the disease to worsen on therapy. Its use increased after 2000 when Docetaxel, for the first time, provided a survival advantage in recurrent disease.

The FDA’s willingness to accept progression-free survival for drug approval was originally based on their expectation that the benefit would be “substantial and robust” but they did not define the term. One group has suggested that improvements should be of the magnitude of 50 percent. Another went even further suggesting a doubling of the survival advantage.

Unfortunately, the trend has been just the opposite. Trials from the 1980s on average gave a 3.9 month improvement, which fell to a meager 0.9 months after 2000.

What are patients and their physicians to make of these trends? First, the large clinical trials, that are so common today, are much more likely to achieve significance. The troubling corollary is that statistical significance is not the same as clinical relevance. The “publish or perish” climate, combined with the skyrocketing cost of drug development has placed inordinate demands upon investigators and their sponsors to achieve “positive results.” Fearing failure, many pharmaceutical companies sponsor “safe” trials that provide incremental advances but few breakthroughs.

Meaningful advances in oncology are generally quite evident. The first use of Interferon alpha for the treatment of hairy cell leukemia provided a response rate of 100 percent and earned a lead article in the New England Journal of Medicine (NEJM) with only seven patients!

Similarly the 57 percent response rate for Crizotinib in ALK positive lung cancer required only 82 patients for a place in the NEJM. Unfortunately, the failure of contemporary investigators to identify more “paradigm changing therapies” has forced many to lower the bar.

The clear solution to the problem is the better selection of candidates for therapy. Despite advances in molecular biopsy a paucity of truly effective companion diagnostics exist. Outside of EGFR, ALK, and ROS-1, it is anybody’s guess how to manage the vast majority of non-small cell lung cancer patients.

While we expand our armamentarium and develop better companion diagnostics, today we can apply measures of cellular response (as found in an EVA-PCD assay)
that capture all of operative mechanisms of sensitivity for all classes of drugs. While it is not always possible to know why a patient will respond, it is possible to know that they will respond. In the words of Judge Stewart, when it comes to a responsive lung cancer patient “I know it when I see it.”

Outliving Hospice

Outliving CancerFor those of you who have read my book Outliving Cancer you will recognize the chapter entitled “Outliving Hospice.” It is the description of one of my lung cancer patients.

The saga began in 2005, when this gentleman with metastatic lung cancer under the care of the Veteran’s Administration in Los Angeles presented to our group requesting a biopsy for an EVA-PCD assay to select therapy. Diagnosed some months earlier his lung cancer had progressed following first line platinum-based chemotherapy. He was deemed untreatable and placed on hospice.

At his request, one of our surgical colleagues conducted a biopsy and identified a treatment combination borrowed from work done some years earlier by Japanese investigators. It worked perfectly for a year allowing him to return to a normal life.

At year two however, he relapsed. At that point, we confronted a dilemma – would we accept the inevitability of his progressive disease, fold our tent, and allow the patient to return to hospice care; or conduct yet another biopsy to determine the next line of therapy? If you have read the book, then you know how the story plays out. The new biopsy revealed the unexpected finding that the tumor had completely clocked around to an EGFR-driven cancer, highly sensitive to erlotinib (Tarceva). Placed upon oral Tarceva, he has been in remission ever since.

When I saw Rick, two weeks ago at our six month routine follow up he provided a copy of his February 2014 PET/CT scans which, once again, RickHelm Small Imagerevealed no evidence of progressive disease. With the exception of the skin rashes associated with the therapy, he maintains a completely normal life. During our discussion he apprised me of an interesting fact. His survival, now approaching 10 years, according to him, constitutes not only the longest survivorship for any patient under the care of the Los Angeles VA, nor any patient under the care of the VA in California, no, he is the longest surviving actively treated metastatic non-small cell lung cancer under the care of the Veteran’s Administration. Period! While I cannot, with certainty, vouch for this fact, I am quite certain that he is among the best outcomes that I have seen.

There are several points to be gleaned. The first is that every patient deserves the best possible outcome. The second is that hospice care is in the eye of the beholder. The third is that patients must take charge of their own care and demand the best possible interventions available. As an aside, you might imagine that a federal agency responsible for the costly care of tens of thousands of lung cancer patients every year would pay attention to results like Rick’s. Might there be other patients who could benefit from Ex-Vivo Analysis for the correct selection of chemotherapeutics?  One can only wonder.

Lung Cancer Response Rates Double – ASCO Presentation

On Sunday, June 6, 2010, I presented “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) at the 2010 ASCO Annual Meeting. Colleagues received the presentation very well, with hundreds of attendees examining the findings.

The data are very exciting. This trial of 29 patients with metastatic (Stage IV) NSCLC achieved a response that was twofold higher than the national average (62 vs. 31 percent: p=0.0003). More striking was the 50 percent improvement of median time to progression (9.5 months vs. 6 months). And most exciting of all, the very excellent survival data with a median overall survival of 22.3 months compared with the national average of 12 months.

The most interesting aspect of this study is the fact that we utilized the very same chemotherapy drugs that are available to all medical oncologists in the United States. The trial was limited to FDA approved, compendium listed agents with specific indications for NSCLC. As such, we did not apply new classes of drugs, yet doubled the response rate and median overall survival.

The implications of this are staggering, particularly when we consider the impact that targeted agents are having on cancer care. I will explore these implications in the next entry when I discuss such agents.