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. . . .

If It is Too Good to Be True . . .

The February 12, 2012, CBS 60 Minutes covered a story that has sparked a great deal of interest among cancer patients and medical professionals. The topic was an investigator named Anil Poti who, while working at Duke University developed a laboratory platform for the study of human lung cancer.

Using molecular profiling, Dr. Poti and his collaborators, reported their capacity to distinguish responding and non-responding cancer patients, providing survival curves that were nothing short of astonishing. I recall attending the original lectures given by these investigators at the American Association of Cancer Research meeting several years ago.

As an investigator in the field of drug response prediction, working in lung cancer I had a particular interest in their platform and I was extremely impressed by the outcomes they reported. At the time, I wondered how the static measurement of gene profiles could possibly characterize the nuances of human biology, to encompass the epigenetic, siRNA, pseudogene, non-coding DNA and protein kinetics that ultimately characterize the human phenotype. Nonetheless, with such compelling data I was prepared to be convinced.

That is until a relatively unheralded report in the Cancer Letter raised concerns by several biostatisticians regarding the reproducibility of Dr. Poti’s findings. And then more comments were followed by a full NIH investigation. A panel of biostatisticians was convened and a formal report provided the explanation for Dr. Poti’s excellent results.

They had been invented. The clinical outcomes were not real results. The findings had been retrofitted to match the patient responses and this was the subject of the 60 Minutes report.

What the 60 Minutes report did not address however, was the real problem. That being the inability of contemporary genetic profiling to truly define human biology. For all the reasons enumerated above, siRNA, non-coding DNA, etc., the simple measurement of gene sequences cannot accurately predict biological behavior. This is what the 60 Minutes reporters and the physicians they interviewed, never discussed. The problem at hand is not an errant investigator but an errant scientific community. Our love affair with the gene that began in 1953 (Watson and Crick) has now been confronted by a most heartbreaking example of infidelity (pun intended).

Genes do not make us what we are; they only (sometimes) permit us to become what we are, with the vagaries of transcription and translation lying between.

This leads us to the reasons I find this so critically important:

1. I cannot stress strongly enough that this is NOT what I do. Genomic analysis (their work) and functional analysis (our work) are distinctly different platforms.
2. I strenuously resist any attempt on the part of anyone to tar me or my work with this brush.
3. It is precisely because genomic analysis cannot accurately predict cancer patient outcomes, that these investigators found it necessary to invent their data.
4. Despite this, functional analyses can and do provide these types of predictive results in lung cancers and other diseases as we have reported in numerous publications.
5. Finally, while imitation is the sincerest form of flattery, this is one instance in which I would prefer to decline the compliment.

English Patients Denied Access to Ipilimumab

Among the more interesting discoveries in recent years have been two breakthroughs in the management of malignant melanoma. One drug, vemurafenib, a tyrosine kinase inhibitor, acts specifically in patients who carry the BRAF (V600E) mutation. The second drug ipilimumab, offered commercially from Bristol-Meyers Squibb as Yervoy, is a monoclonal antibody that acts by blocking CTLA-4, thereby enhancing T-cell response to tumor antigens. While vemurafenib has a somewhat narrow target population, ipilimumab targets may extend to a broader range of melanoma patients and will likely find a role in other cancers.

The data supporting ipilimumab’s use in advanced melanoma was reported in a 2010 Phase III trial, which provided a superior median survival for those treated with the drug over those who received a placebo. Superior one and two-year survivals were also reported. Unfortunately, this did not rise to the level that met the standards of the English watchdog organization, National Institute for Health and Clinical Excellence (NICE). The chief executive of NICE did admit that the drug could “potentially be very effective for a small percentage of patients.” Unfortunately, under current NICE guidelines, that small percentage of patients will not have access to the drug.

This is not the first time that a drug, found effective for the treatment of a subpopulation of patients has been denied approval based upon cost efficacy and the comparatively limited population of patients who stand to gain.

The role of Avastin in breast cancer represents a similar dilemma for those patients who might benefit but cannot afford the out-of-pocket expenses. Indeed, NICE originally denied approval to bortezomib, a highly active drug for the treatment of multiple myeloma, based upon similar cost considerations.

What ipilimumab, Avastin and bortezomib have in common is that they are harbingers of the coming conflict between patients-in-need and society’s capacity to cover the increasing costs of cancer therapy. Cost efficacy questions will only be resolved when we have the capacity to identify likely responders prior to therapy, enabling us to use drugs only in those patients with the highest expectations of response. Marginal overall benefits that come at high price will continue to fail until we redouble our efforts to refine the process of drug selection for individual patients. Janet Woodcock, MD, from the FDA once said, that we need “a critical path” from bench to bedside to guide clinical decisions. The human tumor primary culture functional analyses that we employ can provide that critical path and we would hope limit the need for the broad-brush policy decisions that are being handed down by NICE and similar entities both here in the U.S. and abroad.

Ovarian Cancer Therapy

For many years I have been interested in the ovarian cancer literature. After all, it was our group that originally developed the platinum plus gemcitabine doublet and tested it through a Phase II trial conducted by the Gynecologic Oncology Group (GOG). The study’s results were reported in Gynecologic Oncology in 2006.

I then watched with interest as the GOG 182 five-arm clinical trial unfolded. This international study of over 4,000 patients randomly mixed and matched drug combinations but provided no evidence of superiority of one arm over another. The final conclusion of the manuscript that reported these results (Bookman, MA., Brady, MF, McGuire, WP, et al. J Clin Oncol 27: 1419-1425, 2009), stipulated that carboplatin plus taxol remained the “gold standard” for advanced epithelial ovarian carcinoma. A study of over 900 patients that compared carboplatin plus gemcitabine to carboplatin plus paclitaxel induction (Gordon A, Teneriello M, Lim, P, et al Clinical Ovarian Cancer, 2, 2:99-105, 2009) again provided comparable outcomes between arms yet carboplatin plus taxol remains the “gold standard.”

To this collection of published experiences, we now add the report by Sandro Pignata and co-investigators from the MITO-2 Phase III trial (Pignata, S., Scambia, G., Ferrandina, G., et al. J Clin Oncol 29: 3628-3635, 2011). This clinical trial conducted by Italian investigators compared carboplatin plus taxol to carboplatin plus pegylated liposomal doxorubicin (PLD) known in the U.S. as Doxil. Four hundred and ten patients were randomized to each arm of the trial. The results revealed numerical superiority for the carboplatin plus PLD arm in terms of median progression-free survival (19 months vs. 16.8 months) and numerical superiority for overall survival for the carboplatin plus PLD over the carboplatin plus taxol arm (61.6 vs. 53.2 months). However, these results did not achieve statistical significance. Therefore, the authors conclude that carboplatin plus taxol “remains the standard first-line chemotherapy for ovarian cancer.” While they do grant that, based on toxicity, carboplatin plus PLD could be considered as an alternative therapy.

With the GOG 182 study, the Gordon study (comparing carboplatin plus gemcitabine) and the most recent Pignata study comparing carboplatin plus PLD all establishing activity for several first-line regimens, why is it that the gynecologic oncologists continually return to carboplatin plus taxol as the “gold standard?”

Is there not ample evidence that several regimens provide similar results and survivals? Is there not evidence that the toxicities differ? Why can’t the gynecologic oncologists get off the dime? Why can’t they admit that several treatment regimens are appropriate and indicated for the malignancy? Why can’t they admit that some patients may, in fact, do better with one treatment over another?

And, finally, why can’t they admit that using laboratory analyses to determine a patient’s functional profile has the potential to select amongst these regimes to provide the best outcomes for the majority of patients?

Is There a Role for Maintenance Therapies in Medical Oncology?

There is a long tradition of maintenance therapy in pediatric oncology. Children with acute lymphoblastic leukemia uniformly receive three stages of therapy: induction, consolidation, and finally maintenance. The maintenance stage consists of weekly, or even daily therapies.

The historical experiences of relapse in this population lead investigators to consistently expose these patients to drugs for a period of years. Despite the apparent success of this approach in childhood cancers, long-term maintenance therapy did not gain popularity in adult oncology. Why?

There are probably several reasons. One reason is that childhood leukemia is among the most chemo-responsive diseases in medicine. As such, there are many active drugs available for treatment and many non-cross-resistant maintenance schedules that can be employed.

A second reason is the relative tolerability of drugs like oral thioguanine or mercaptopurine that are used in chronic maintenance therapy. By contrast adult tumors rarely achieve complete remissions. The number of active drugs has historically been very limited and the tolerance of long-term treatments characteristically poor.

Despite this, there is an appealing rational for maintenance therapy. Once we recognized and incorporated the tenents of apoptosis and programmed cell death into cancer management, we were forced to reconsider many of the principles of older treatment protocols.

Conceptually, maintenance allows for a cytotoxic exposure when the cell enters a “chemosensitive” period in its life cycle.  Cancer cells that are “out surviving” their normal counterparts often do so in a quiescent stage (G0 Gx). In order to capture these cells, drugs must be present in the body when these cells awaken from their dormancy. As we have now achieved increasingly durable remissions in diseases like breast cancer, small cell lung and ovarian, we are confronting patients in long-term complete remission. When you add to this newfound population the availability of comparably mild agents, like the low dose Gemcitabine/Cisplatin doublet, we now have at our disposal active drugs that can be safely continued for long periods of time.

Using laboratory selection to identify first line (induction), second line (consolidation) and finally third line (maintenance) schedules, we can now offer our patients well-tolerated combinations that offer the hope of more durable remissions.

The GOG 178, in which continued taxol dosing provided more durable remission in ovarian cancer, provided the first inklings of this. Unfortunately, taxol is toxic. And the more durable remissions came at an increasingly high price: neuropathy, myelosuppression, alopecia, fatigue and malaise, which greatly limited the utility of this approach. Yet it does not limit its theoretical attractiveness as we continue to develop targeted agents with more selective activity and modified toxicity profiles. We anticipate maintenance therapies will become more widespread.

Based upon our experiences to date, we are successfully using this approach with our patients who achieve good clinical remissions.

Recurrent Small Cell Cancer of the Lung: A Therapeutic Challenge

I recall as a junior medical oncology Fellow, one of my senior Fellows describing small cell cancer of the lung as “leukemia of the lung.” The reason he used this description was because leukemia is among the most rapidly progressive and aggressive forms of cancer.

Arising in the bone marrow, an afflicted patient’s white blood cell count can double every day, a remarkable achievement when one considers the hundreds of billions of cells involved. What this doctor meant was that the lung cancer of small cell type (also known as oat cell), grew so rapidly that in untreated patients, survival can be measured in weeks to months. With the discovery of effective chemotherapy this disease became a comparatively easy mark for the treating oncologist. Ironically, where it was the worst form of lung cancer during the 70s, by the 1990s it was the best form to have. Most patients responded to treatment and some lived years. The problem is, treating patients who recur.

For unknown reasons this otherwise chemosensitive disease has a tendency to recur with a vengeance. Attempts to control recurrent disease with second line therapies have characteristically been unsuccessful. Drug combinations that are generally quite active in the first line setting, are almost universally inactive in second line use.

As a result, recurrent small cell lung cancer is tantamount to a death sentence.

Two months ago, a slender woman arrived at Rational Therapeutics carrying a biopsy kit and a bottle filled with straw-colored fluid. She explained that her husband had recurrent small cell lung cancer and his surgeon had inserted a chest tube. He then provided us with both biopsy material and fluid. She went on to say that she herself was a laboratory scientist and was familiar with laboratory techniques.

We processed the specimen, which provided amble cells for analysis. Not surprisingly, the tumor was resistant to many (most) of the drugs tested. However, the class of drugs known as alkylating agents revealed persistent activity. More importantly, the combination of an alkylating agent and topotican revealed activity and synergy.

Having published a paper on this topic several years ago, (Nagourney et al, British Journal of Cancer 2003) I was quite familiar with this combination. Referencing work by investigators at Yale University, using the combination of cytoxan and topotican, I provided my recommendation to a colleague who administered this combination with a very tolerable weekly dose schedule.

The patient responded immediately. So much so, that between cycle one and cycle two he took a vacation to San Diego with his wife.  Further response was documented following cycle two.  Most gratifying has been the very limited amount of toxicity in the treatment itself.

Looking Forward to TEDxSoCal

I remember my first recollection of the TED (Technology Entertainment Design) conferences, which have been held annually for almost two decades. Drawing together innovators in a broad spectrum of disciplines, these programs have become an institution unto themselves. With invited speakers ranging from Harvard’s Edward O. Wilson to business leaders, like Microsoft’s Bill Gates, the lectures cover a panoply of interesting topics.

It was with a sense of delight that I received an invitation to speak at the TEDxSoCal conference on July 16 at the Long Beach Terrace Theater. As the date approaches, I am looking forward to the event with great anticipation. Since the event is sold out, I understand I’ll have 800 attendees in the audience.

What an interesting opportunity to engage this group in a discussion of cancer biology with our focus on biochemistry and metabolism. This is timely in the context of Gina Kolata’s recent article in the New York Times on the failures of genomics platforms in the field of functional profiling for cancer treatment.

I will report next week on this experience.

The Avastin Saga Continues

We previously wrote about bevacizumab (Avastin) and its approval for breast cancer. The early clinical trials revealed evidence of improved time to disease progression. This surrogate measure for survival benefit had, over recent years, gained popularity, as time to disease progression is a measure of the impact of a given treatment upon the patient’s response durability. It was hoped and believed that time to progression would be an early measure of survival.

Unfortunately, the survival advantage for the Avastin-based therapies in breast cancer has not met statistical significance. As such, careful review by the oncology drug committee of the FDA lead to a unanimous decision to remove Avastin’s indication in breast cancer. Avastin has not been removed from the market, but instead, cannot be promoted or advertised, nor do insurers necessarily reimburse it. This decision, however, will have a very big impact on Medicare patients and many others who are in managed care programs (HMOs).

There are no villains here. Instead, dedicated physicians empowered to scrutinize the best data could not prove beyond any doubt that the drug improved survival. The time to progression data was favorable and the survival data also trended in a favorable direction. But, the final arbiter of clinical approval — statistically significant survival — was not met.

The physicians who want to provide this for the patients, the company that produces the drug and the patients who believe it offers benefit all have legitimate positions. As Jerome Groopman, MD, once said, in a similar situation with regard to the FDA approval of interleukin 2 (a biological agent with profound activity in a small minority of melanoma and renal cell cancer patients), “I am confronted with a dilemma of biblical proportions, how to help the few at the expense of the many.”

The Avastin saga is but one example of what will occur repeatedly. The one-size-fits-all paradigm is crumbling as individual patients with unique biological features confront the results of the blunt instrument of randomized clinical trials. Our laboratory has been deeply involved in these stories for 20 years. When we first observed synergy for purine analogs (2CDA and fludarabine) with cytoxan, and then recommended and used this doublet in advanced hematologic malignancies (highly successfully, we might add) we were a lone voice in the woods. Eventually, clinical trials conducted at M.D. Anderson and other centers confirmed the activity establishing these treatments as the standards of care for CLL and low-grade lymphoma.

The exact same experience occurred in our solid tumor work when we combined cisplatin plus gemcitabine in pancreatic, ovarian, breast, bladder, lung and other cancers. While our first patient (presumably the first patient in the world) received cisplatin plus gemcitabine for drug-resistant recurrent ovarian cancer in 1995 — providing her an additional five years of life — it wasn’t until 2006 that the FDA approved the closely related carboplatin plus gemcitabine for this indication.

We now confront an even greater hurdle. With our discoveries, using novel combinations of targeted agents, we are years (perhaps decades) ahead of the clinical trial process. We know that patients evaluated in our laboratory with favorable profiles can respond to some of the newest drugs, many of which have already completed Phase I of clinical trials. It is our fervent belief that we could accelerate the drug development process if we could join with the pharmaceutical companies and the FDA to put these hypotheses to a formal test.

Again, there are no villains here. Patients want, and should, receive active drugs. Doctors should be allowed to give them. The drug companies want to sell their agents and the FDA wants to see good therapies go forward.

The rancor that surrounds these emotionally charged issues will best be resolved when we introduce techniques that match patients to active therapies. We believe that the primary culture platform used in our laboratory, and a small number of dedicated investigators like us, may be the answer to this dilemma.

We will redouble our efforts to apply these methods for our patients and encourage our patients to lobby their health care insurers and representatives to sponsor these approaches. To date, we have been unsuccessful in convincing any cooperative group to test the predictive ability of these selection methodologies. In response, I reiterate that I will gladly participate and, to the best of my ability, support at least the laboratory component of any fair test of our primary culture methodologies.

We stand at the ready for the challenge.

There is More to Gastrointestinal Cancer Management Than FOLFOX

Several months ago, I was introduced to a 58-year-old gentleman with a very bad diagnosis — a bout of gastrointestinal bleeding that had lead to an upper GI endoscopy. It wasn’t an ulcer, or even gastric cancer, but a very rare form of cancer arising in the duodenum. Adenocarcinoma of the duodenum is very uncommon.

This patient was in trouble.

In addition to the bleeding, he had lost a substantial amount of weight, was in pain and had a very large tumor that was nearly obstructing his upper GI tract. After getting the patient stabilized in September 2010, he was referred to a surgeon who conducted an aggressive surgical resection. The recovery was difficult, prolonged and accompanied by additional GI bleeding. By the time the patient had recovered adequately enough to consider additional therapy, his PET scan revealed extensive re-growth.

If you were to ask medical oncologists in the United States what to give such a patient, 99 percent would recommend FOLFOX or some variation thereof. But, FOLFOX wasn’t the right treatment for this patient. Instead, he had a strong signal for Irinotecan, which was further enhanced by the addition of an EGFR inhibitor. Based on this, I elected to treat the patient with Erbitux + Irinotecan. Before starting therapy, his CA 19-9 was 354. Although his signal for the EGFr inhibitor was very favorable in our analysis, I screened him for K-ras mutation. It seemed evident from his dose response curves and clear synergy between Irinotecan and the EGFR inhibitors that he would be K-ras wild type, but in this era of evidenced-based medicine one must be politically correct.

Indeed, he was K-ras wild type and we started treatment with Erbitux + Irinotecan. Other than the rash associated with the Erbitux, the tolerance was good. The bleeding stopped immediately, the CA plummeted with the first dose to 71 and the patient then returned every other week for therapy.

On February 11, 2011, three cycles later, we repeated the PET/CT. The phrase “marked interval regression” of measurable disease caught my eye. I also noted the normalization of his CA 19-9. The patient had gained weight and returned to normal activities. With the exception of a small and diminishing rash, he looks quite normal. In fact, with the rather modest dose of Irinotecan used in his schedule, he hasn’t even suffered any hair loss. What I find most interesting about this patient is that FOLFOX, the most widely used regimen in this setting, wasn’t anywhere on the radar screen. It wasn’t active, it wasn’t recommended and I feel confident it wouldn’t have worked. However popular FOLFOX may have come to be in patients like this, it doesn’t fit everyone.

A Pancreatic Cancer Patient – Seven Years Later

More than seven years ago, I was asked to see a patient in consultation. This vigorous 54-year-old gentleman had already undergone a Whipple procedure for the treatment of a pancreatic carcinoma. His skilled-surgeon had resected most of the tumor, but could not clear the margins. With each successive attempt, he identified additional tumor. Unable to achieve a complete surgical resection, the patient was closed, recovered and visited me for a discussion of therapeutic options.

We identified a two-drug combination to be used in conjunction with external beam radiation, a regimen that few — if any — investigators would have suggested. Adjusting the doses to achieve a tolerable schedule, he completed the entire course of therapy with acceptable toxicities. Contrary to his surgeon’s expectations, the patient achieved a complete and durable remission. He returned to his active lifestyle, remarried and became an advocate for the aggressive management of pancreatic cancer.

Now, seven and a half years later with a rising CA 19.9, he is identified to have a focus of uptake on PET CT in the body of the pancreas. A surgical exploration to remove the tumor provided adequate tissue for an EVA-PCD analysis. The patient was once again tested against the standard therapies used in this setting. Among the drugs we examined are the EGFR inhibitors, the taxanes, the combination of EGFR inhibitor + gemcitabine and the platinum + 5FU combination. Each one of these would be a reasonable choice. Indeed, FOLFOX, Tarceva + gemcitabine, the GTX regimen and — most recently — Taxol-gemcitabine based combinations, would all be favored choices for medical oncologists in the U.S. today. Yet, this patient was sensitive only to cisplatin + gemcitabine and none of the others.

Following publications from a group in Scottsdale, Arizona, many oncologists are utilizing Taxol + gemcitabine. There are proponents for Tarceva + gemcitabine, and those who prefer FOLFOX. At least for this patient, none of them would’ve been right. Interestingly, after more than seven years later the patient’s profile reflects the same combination that was used initially. It is interesting to ponder, based on this finding, whether this is a new primary or a sanctuary-site recurrence with so long a disease-free interval to remain sensitive to the platinum-based combination. We now hope to provide him seven and a half more excellent years… at the very least.