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.

What’s the Best Treatment for Metastatic Colorectal Cancer?

The answer is: nobody knows.

We have previously described a patient with a small bowel cancer for whom a treatment regimen contrary to the most widely used triplet was recommended. While it is arguable that small bowel adenocarcinoma is rare enough that no one really has a favorite regimen, colorectal management has become somewhat rigidly focused on FOLFOX. Yet, this popular combination may not be right for every patient with colon cancer.

We know, for example, that FOLFOX combined with Avastin provided no advantage in the adjuvant setting. We also know that the random addition of Erbitux to FOLFOX similarly failed to provide an advantage. As the modes of action differ between drugs, it is not surprising that subsets of colon cancer patients may do better with Irinotecan based therapies. Indeed, clinical trials combining the new monoclonal antibodies with Irinotecan have proven quite favorable, including the 2007 BOND-2 trial reported by investigators at Memorial Sloan Kettering in New York.

With this in mind, patients who present with both untreated colon cancer and a favorable profile for Irinotecan based combinations always interest us. One such patient presented to our attention in the last few weeks. This patient, in his mid 30s, was found to have inoperable, widely metastatic disease with extensive liver involvement. Confirmatory biopsies provided tissue for analysis and revealed no evidence of mismatch repair.

The results of the EVA-PCD platform were interesting on many levels. First, the EGFr active drugs provided a uniquely favorable profile, as did the down-stream inhibition of the MEK-ERK inhibitor we studied. These findings strongly suggested that the patient was RAS wild type (i.e. non-mutated). It is known that RAS mutation confers resistance to the EGFr active drugs. By inference, his sensitivity to the EGFr active drugs was prima facie evidence of RAS wild type, a finding that was confirmed later by molecular analysis. There was also a favorable profile for VEGF active drugs. Most favorable of all was the combination of Irinotecan with inhibitors of both VEGF and EGFr. This was the regimen that we selected.

We wait with interest the results of the therapy, as re-staging for response will be conducted in the coming months.

Not Responding to the Standard Cancer Treatment? Maybe You’re an Outlier

In a recent reply to a blog comment, I mentioned the term “outlier” to describe a woman with breast cancer who had an excellent response to bevacizumab-based therapy. This was part of a discussion about the drug and its role in cancer treatment. The term outlier was utilized to describe this woman’s excellent response to a drug combination that has not achieved statistically significant survival advantage in the general population of breast cancer patients.

While outliers may connote strangeness or removal from the norm, in contemporary cancer therapies being removed from the norm can be a very, very good thing. After all, a minority of cancer patients benefit durably from chemotherapy. Those patients fortunate enough to have long-term responses are the happy outliers who populate the scientific community’s grab bag of anecdotes.

However, to the individual patient, a good response is much more than an anecdote, it is a life saving experience, an experience that every cancer patient richly deserves. While clinical trials are designed to identify average improvements for average patients, virtually every trial conducted has patients who live much longer than average. They constitute the tail on the survival curve and almost every trial has several.

Our job should be to identify those true responders and treat them appropriately rather than denying them active treatments based on the failure of the average patient paradigm. In statistics, the term applied for these failures are “beta errors,” meaning that the investigators missed the benefit of a given treatment. By identifying active treatments in small subsets of patients, functional analytic tools (like the Rational Therapeutics EVA-PCD platform) enable us to select those small subsets for treatment regardless of average expectations.

Novel Cancer Treatments — Crizotinib

Recent reports have described the striking activity of a novel Pfizer compound known as Crizotinib. The compound is an inhibitor of an enzyme known as the anaplastic lymphoma kinase (ALK). In approximately 5 percent of non-small cell lung cancer patients, a specific mutation known as the EML4-ALK rearrangement results in activation of this gene and the development of cancer. In those patients who are found positive for this mutation, the response rate to the drug Crizotinib is 57 percent with a disease control rate of 87 percent at eight weeks.

Hailed as an unprecedented response rate by Anil Potti, MD, associate professor of medicine at Duke University, these results reflect the power of pre-selection of candidates for treatment. The drug is reasonably well tolerated and represents a true advance. Taken in context, however, these results are not superior to those that we recently reported using conventional chemotherapies pre-selected by functional analysis. Indeed, our results with a response rate of 62 percent, a time to progression of 9.5 months and a median overall survival of 20.3 months are actually better. More notably, our results were obtained with conventional chemotherapeutics, not novel compounds.

What is most striking about the Crizotinib results is the capacity of pre-selection to demonstrably improve response rates. Yet, these results only apply to a distinct minority of patients. The results that we reported at ASCO reflect the activity of chemotherapy applicable to the remaining 95 percent of NSCLC patients. It is also highly likely that functional analysis will select Crizotinib candidates as well, or better, than the mutational analysis utilized for patient selection in the study reported. For comparison, our response rates for erlotinib (Tarceva) as a single agent are superior to the response rates for patients selected based on EGFR mutational analysis. In addition, secondary mutations have already been identified that confer resistance to Crizotinib, which likely confound durable remissions for this and related drugs.

While I applaud the results of this interesting trial, my team and I feel it important that all lung cancer patients have the benefit of pre-selection. Whether they fit into the 5 percent described in this report, or the 95 percent covered in our clinical trial.

There is Nothing New Under the Sun

The most sophisticated Western medical centers, purveyors of allopathic medicine, spent decades denigrating natural products as “quackery.” Nutritional supplements, antioxidants and natural extracts were viewed as the purview of hippies and nuts. Yet, a brief examination of the most active compounds in cancer therapy today quickly establishes how wrong-headed this mindset was. In addition to the taxanes (extracts of taxus brevifolia and taxus baccata), the camptothecins (extracts of camptotheca acuminata), the vinca alkaloids and the epothilones, are host of simple small molecules like retinoids, platins and arsenic trioxide.

As Western scientists have developed a greater understanding of cellular circuitry and cancer metabolism, they have been dragged, kicking and screaming, to the admission that nature is indeed the best organic chemist.

Recent reports of a Chinese herb combination called PHY906 are but the latest example of this reality. Careful analysis reveals PHY906 — a combination of four herbs — contains 64 compounds including flavonoids, saponins and monoterpenes. As an editor of the Journal of Medicinal Foods, I have published and edited many articles on related topics. The terpenes are among the most important and ubiquitous bioactive compounds found in nature, with effects on cholesterol metabolism, Ras gene signaling, and mitochondrial function.

PHY906 is one more example of the adage that “there is nothing new under the sun.”

Synergistic Drug Combinations Provide Better Outcomes for Cancer Patients

Among the most sought after attributes of chemotherapy drug combinations is drug synergy. Synergy, defined as supra-additivity wherein the whole is greater than the sum of the parts, reflects an elegant interaction between drugs predicated on their modes of action. While some synergistic interactions can be predicted based upon the pharmacology of the agents, others are more obscure.

We have extensively examined the synergy between classes of drugs based on known modes of action. But, in some circumstances, our studies have been purely exploratory. Among our most successful findings have been:

  1. Alkylating agent plus purine analogs (cytoxan & fludarabine)
  2. Platin plus antimetabolites (cisplatin & 5FU; cisplatin & gemcitabine)
  3. Dual antimetabolite combinations (gemcitabine & capecitabine)
  4. Natural products plus anti-metabolite (Doxil & gemcitabine; vinorelbine & capecitabine)

More recently, we have explored the interaction between signal transduction inhibitors. The results of these investigations have been the subject of numerous presentations at international meetings.

The application of synergy analyses may represent one of the most important applications of our functional profiling platform; enabling us to explore both anticipated and unanticipated favorable interactions. Equally important may be our capacity to study drug antagonism wherein two effective drugs counteract each others’ benefits. This phenomenon, characterized by the whole being less than the sum of the parts, represents a major pitfall for clinical trialists who simply combine drugs “because they can.”

These analyses are revolutionizing the way our group applies newer classes of drugs and has the potential to accelerate drug development and clinical therapeutics. Good outcomes require good drugs, but better outcomes require good combinations. Intelligent combinations are a principle focus of the work at Rational Therapeutics. We strive everyday to identify the best outcomes for patients.