Cancer and the Great Divide

There are two types of cancer patients: those we can treat and those we can’t. As I reflect on this year and the years past during which we have applied the process of laboratory-guided treatment, I am reminded of this fact.

The EVA-PCD functional profile enables us to choose active treatments for patients, but I have sometimes wondered whether we are, in fact, choosing patients for the available drugs.  While the end result may not be all that different, e.g. superior clinical outcomes over randomly administered (standard) therapies, the path to that outcome, leaves room for interesting discussion.

I first pondered this issue at the time of completion of our earliest study. That study was conducted in childhood acute lymphoblastic leukemia (ALL). Recognizing that the corticosteroids were among the most important drugs for ALL, we exposed freshly isolated lymphoblasts from ALL patients to dexamethasone (ex vivo). At the fourth day we measured the degree of cell death and separated the patients in “sensitive” and “resistant “ subgroups. Strikingly, those children whose lymphoblasts died in the laboratory following exposure to dexamethasone (ex-vivo), virtually all survived without relapse, while those children whose lymphoblasts did not die in the laboratory following dexamethasone exposure (ex-vivo) relapsed at an alarming rate with only 25 percent still alive at the sixth year of follow up (p=0.009).

What we had succeeded in doing by Day 4 of diagnosis was something that all the known prognostic factors, like age, WBC and male vs. female could not do, namely accurately identify the responders and survivors.

Today, when I test patients in our laboratory, I consistently double or even triple the response rates over standard protocols, yet a subset of patients are not found sensitive to the available therapies. Patients who do not respond to chemotherapy are today known, in the oncologic vernacular, as “failing therapy.” If we view these “non-responders” as a biologically distinct group (not unlike the dexamethasone-resistant ALL patients above) then our role, in the field of functional profiling, is to quickly segregate the responders (to available drugs) from the non-responders and move those “non-responders” immediately to something that will work for them. In this light, patients no longer “fail therapies” but instead “therapies fail patients.” It is then our mandate to use the ex-vivo platforms to find (and yes, discover) novel therapies and combinations that will meet their unmet need.

As the New Year is upon us I am filled with the expectation that 2013 will be one of discovery and innovation. Never before have so many interesting compounds been available for study. If we are fortunate enough to succeed in our efforts to collaborate with members of the drug development community and have the opportunity to intelligently apply functional profiling, for drug discovery, 2013 could be a very good year indeed.

Phar Lap and the Treatment of Leukemia

Phar Lap (1926-1932) was a thoroughbred horse bred in New Zealand. After winning the Melbourne Cup and 37 other races, his victory at the Agua Caliente racecourse in Tijuana, Mexico, established the track record in 1932.

With each victory, his detractors became more strident. He was even the target of an assassination attempt. To prevent him from winning (and thereby disrupting the betting odds) officials would add lead bricks to his saddle. On the occasion of the Melbourne cup of 1930 he carried 138 pounds of lead, yet won the race. A quote from the Sydney Morning Herald dated Wednesday, November 5, 1930, read, “The question was not which horse could win, but could Phar Lap carry the weight. Could he do what no other horse before him had done?”

It appeared that the one thing that race officialdom feared above all else, was a horse that could consistently beat the field and win the race.

The tale of Phar Lap was brought to mind after a colleague forwarded a paper published in the journal Leukemia on August 10, 2012: “The use of individualized tumor response testing in treatment selection: second randomization results from the LRF CLL4 trial and the predictive value of the test at trial entry.” (E Matutes, AG Bosanquet et al, Leukemia, Letter to the Editor.)

Published as a letter to the editor, the paper describes correlations between the TRAC (tumor response to antineoplastic compounds) assay, a short-term suspension culture cell death laboratory assay (very similar to our work) and clinical response, time to progression and overall survival in patients with chronic lymphocytic leukemia (CLL) who received chemotherapy as part of the LRF CLL4 trial conducted in England between 1999 and 2004.

The initial trial was a blinded correlation between laboratory assay results and patient response to one of three treatment regimens. An examination of the data reveals a clear and statistically significant correlation between drug sensitivity and overall survival (p = .0001). The 10-year survival of drug sensitive patients was 28 percent, while the 10-year survival for drug resistant patients was 12 percent.

Significant correlations with survival were observed for known prognostic factors like 17p and 11q deletion, as well as IGHV mutational status. Correlations were also observed between the TRAC assay results and these prognostic factors.

The report goes on to describe a second randomization that took place at the time of disease progression, either failure of first-line therapy or reoccurrence within 12 months. In this part of the study, 84 relapsed patients were allocated to standard therapy and their outcomes were compared with 84 patients allocated to treatment guided by the TRAC assay. The drugs tested in the assay-directed arm included chlorambucil, cytoxan, methylprednisolone, prednisolone, vincristine, doxorubicin, mitoxantrone, 2CDA, fludarabine and pentostatin. In vitro resistance for combinations was defined as resistance to all constituent drugs in the combination, while drug sensitivity was defined as TRAC-assay sensitivity for any of the drugs used in combination. No discussion of synergy analysis was included.

In examining this study, I cannot help but be reminded of Phar Lap. First, marshaling a study of 777 CLL patients, and conducting 544 TRAC analyses, is a phenomenal undertaking for which these authors should be commended.

Second, the observation of a significant correlation between laboratory assay results and overall survival, as well as the biological implications of this platform’s capacity to correlate with molecular markers is a demonstrable and noteworthy success, however unheralded.

Where the analogy with poor Phar Lap’s struggles, weighted down with lead, becomes most poignant is the final portion of the study wherein 84 patients received assay-directed therapy. To wit, we must remember that in 2012, drug refractory CLL remains an incurable malignancy (with the exception of a small subset of successfully transplanted patients) and that no chemotherapy-alone trial has provided a survival advantage in this group. But this only begins to explain this trial’s results.

Among the virtually insurmountable hurdles that these investigators were forced to confront was the fact that fully 52 percent of the standard treatment arm group were destined to receive fludarabine. This drug, the current gold standard for previously treated patients who fail chlorambucil (constituting 73 percent of the patients in this part of the trial), has an objective response rate of 48 – 52 percent in this population. As the drug would likely be identified as active in vitro as well, this had the impact of pitting the assay arm and the standard arm against one another, frequently using exactly the same treatment.

While this does not mean that the assay arm could not succeed, it does have an enormous impact upon the sample size calculations used to determine the number of patients required to achieve significance.  No pharmaceutical company would ever allow a registration trial to be conducted against an “unknown” control arm, particularly one using the same therapy as the study arm – not ever! Despite these burdens, the assay-directed arm had a superior one-year survival, while virtually all other trends favored the group who received assay-selected therapy. The results of this study are worthy of recognition and further support the clinical relevance, predictive validity and importance of functional analyses. Yet, this interesting study in CLL is unceremoniously relegated to the status of a Letter to the Editor in Leukemia. Perhaps, like Phar Lap, no one really wants to upset the odds.

A Tale of Two Trials

As I read through the November 10 issue of the Journal of Clinical Oncology there were two very different but highly instructive reports.

They first examined the impact of gemtuzumab ozogamicin for patients with acute myeloid leukemia. The second involved the incorporation of bevacizumab and erlotinib into the treatment of Stage III NSCLC in combination with radiation.

By way of introduction, gemtuzumab ozogamicin (GO) is an anti CD33 antibody linked to the highly toxic chemical calicheamicin. Calicheamicin, a member of enendyne class, is among the most toxic substances known to man. By linking this poison to an antibody directed against leukemia cells, it was reasoned that this novel conjugant would provide an effective therapy for leukemia. And indeed it did. But despite compelling science and what appeared to be initially good results (particularly in older patients with AML), and FDA approval for the agent, the drug was withdrawn from the market. Now, with the publication of a new study from the United Kingdom, GO is once again in the limelight as its inclusion in induction therapy resulted in a statistically significant three-year relapse-free survival advantage (p=.0007) and three year overall survival advantage (p=.05).

It appears, with regard to GO, that the clinical trial process failed to identify the clinical utility of an active and novel form of therapy for a potentially lethal disease.

The second article of interest regards a pilot study that incorporated an anti-VGEF antibody (bevacizumab) with EGFR TKI (erlotinib) along with chemotherapy and radiation. In this trial the objective response rate of 39 percent, median progression-free survival of 10.2 months and median overall survival of 10.4 months, were not demonstrably superior to contemporary results, yet toxicity was significantly enhanced. The investigators recommended against further exploration of this combination. Here the aggressive integration of targeted and conventional therapies proved a misadventure.

While these two reports are very different, they represent similar failings of the contemporary clinical trial process. The GO experience reflects the failure to identify efficacy due to contemporary clinical trial’s dilution of the benefit in select candidates, mixed in the overall population, with limited responsiveness to the agent. The second trial represents clinicians’ desire to engage in theoretically attractive clinical trials only to find that they reflect ineffective and/or more toxic treatment regimens.

On one hand, laboratory models that accurately identify responders can segregate those most likely to benefit from those who will not. GO represents just one of many interesting new classes of drugs for whom selective methodologies could prove highly valuable. The lung cancer experience reflects the failure of the research community to dedicate adequate resources to predictive clinical models.

Combinations of chemotherapy with target therapies have been the subject of investigation in our laboratory for more than a decade. For example, we observed antagonism between platins and the EGFR antagonists (gefitinib and erlotinib) two years before publication of the unsuccessful INTACT I and II Trials and three years before the unsuccessful TALENT and TRIBUTE trials.

All four of these trials combined platin based doublets with EGF-TKI’s. More recently we successfully identified favorable interactions between erlotinib and VGEF inhibitors in individual patients that have provided durable responses in our NSCLC patients as first line therapy, now out to four and five years since diagnosis. These experiences represent opportunities to explore novel therapies and avoid inadvertent antagonisms and misadventures.  In the recent JCO, a good treatment was missed while a bad treatment was advanced.

Functional profiling through use of the EVA-PCD® assay may represent the “critical path” from bench to bedside that the deputy director of the Center for Drug Evaluation and Research at the Food and Drug Administration, Janet Woodcock has described as a crying need.