What’s Wrong with Avastin?

Nothing really. It’s a wonderful drug that incorporates the brilliant insights originally articulated by Judah Folkman, MD, at Harvard University. Dr. Folkman reasoned that:

1. Cancers require oxygen and nutrients
2. These would need to be delivered by a blood supply
3. Tumors would avidly seek their own blood supply via humoral factors.

His groundbreaking work ultimately lead to the discovery of VEGF, as well as the FDA approval of Avastin, the monoclonal antibody that binds and inactivates circulating VEGF in patients. The problem isn’t with Avastin, it’s with the practice of oncology – the clinical trial process and the muddied waters that surround clinical utility of any drug, new or old.

There are no perfect drugs. There are simply drugs that work for certain patients. VEGF down-regulation is an attractive and highly appropriate therapy for a subset of cancer patients with many different diagnoses whose tumors use the VEGF pathway to their advantage. Avastin combined with carboplatin and taxol has improved the survival of lung cancer patients. Avastin plus folfox has improved survival for colon cancer patients. Avastin plus chemotherapy improves the survival of some breast cancer patients. The problem is that it doesn’t improve the survival of all breast cancer patients.

When the FDA rules on the clinical utility of a drug, they use a broad-brush approach that looks at the global outcomes of all patients, determining whether these glacial trends reflect a true climate change. The problem is that while Bethesda, Maryland may not be noticing significant changes in ocean levels, people who live on the Maldives are having a very different experience. As these scientists ponder the significance of Avastin, some breast cancer patients are missing out on a treatment that could quite possibly save their lives.

One breast cancer patient’s life saving therapy is another’s pulmonary embolism without clinical benefit. Until such time as cancer patients are selected for therapies predicated upon their own unique biology, we will confront one Avastin after another. Our solution to this problem has been to investigate the VEGF targeting agents in each individual patient’s tissue culture, alone and in combination with other drugs, to gauge the likelihood that vascular targeting will favorably influence each patient’s outcome. Our results to date in patients with non-small cell lung cancer, colorectal cancer and even rare tumors (like medullary carcinoma of the thyroid) suggest this to be a highly productive direction for future development.

The I-SPY 2 Clinical Trial

For those of you who read the Wall Street Journal, an article appeared in the Friday, October 1 issue that described the I-SPY 2 (investigation of serial studies to predict your therapeutic response with imaging and molecular analysis 2) clinical trial. This is an adaptive phase II trial designed to facilitate the introduction of new forms of therapy into clinical practice.

The reporter presents the trial as a dramatic advance, suggesting that the era of “personalized care” is finally upon us. I applaud the intent of a trial to apply “window therapy” (i.e. using the window of time before definitive intervention to introduce and test new therapies) to facilitate drug introduction. However, despite the author’s enthusiasm, the design and application of this trial is demonstrably less than meets the eye.

I-SPY2 uses several molecular markers and established prognostics in conjunction with a new molecular profile (mammaprint) to subgroup candidates prior to randomization. The randomization then allows patients to receive either a standard treatment, or one of five investigational drugs combined with standard agents. Sophisticated imaging technologies are used as surrogates for clinical response, while additional biopsies will provide insights into genomic events.

What this trial does not do is utilize molecular markers (beyond those already available to most clinicians) to select patients for therapy. As such, despite the WSJ author’s glowing review, the trial is, at its core, a randomized selection of candidates. While it may enable the investigators to interrogate the tissue biopsies to answer scientific questions of interest, it does so with no immediate benefit to the patients who participate. Indeed, patients who gain benefit (after being randomized to the investigational arm and then receiving a new combination that actually works) receive said benefit by what could best be described as blind luck. The suggestion that this is “personalized care” falls flat when one realizes that a good outcome is nothing more than a chance event!

Truly personalized care represents the application of validated predictive models to select candidates for specific therapies. Good outcomes can then be ascribed to the intelligent selection and application of effective treatments. The cancer research community’s single-minded focus on genomic platforms, to the exclusion of functional platforms, forces patients to continue to participate in “randomized” trials to test hypotheses of interest to the investigators, largely at the expense of the patients in need. These types of advances could be more rapidly made utilizing functional profiles, such as the one offered at Rational Therapeutics.

What these genomic investigators are expecting their patients to say to them is “You may not be able to treat me any better, but I like the way you think.” What informed patients should be saying instead is, “I don’t care how you think. I want you to treat me better!”

Chronic Lymphocytic Leukemia (CLL) as a Platform for Functional Profiling

Among the most common forms of leukemia in adults is chronic lymphocytic leukemia. This neoplasm usually arises in a subset of lymphocytes known as B-cells. However, T-cell variants also occur. The disease presents clinically as an elevation of the circulating lymphocytes. This may be associated with enlarged lymph nodes, splenomegaly or liver enlargement.

The decision to treat patients is largely based upon clinical staging systems know as the Rai or Binet classifications. Low risk patients can often be observed without treatment, while more aggressive presentations (such as those associated with anemia and low platelet counts) require intervention. More recently, molecular determinants of aggressiveness have been applied in the prognosis of this disease. These include: CD38, VH gene mutation and Zap 70. Additional findings include ATM mutations, principally in the T-cell and pro-lymphocytic variants.

For more than 40 years, the treatment of choice for this disease was oral chlorambucil. Although effective, chlorambucil resulted in the development of resistance and was associated with rather significant myelosuppression over time. The introduction of fludarabine (FAMP) and 2-CDA revolutionized the management of this disease —providing high response rates with relatively tolerable toxicities.

The introduction of 2-CDA and fludarabine in the 1980s offered an opportunity for our laboratory to examine drug interactions in CLL patients. Combining the alkylating agents (of which, chlorambucil is a member) with 2-CDA revealed synergy (supra-additvity) in 100 percent of the CLL samples we studied (Nagourney, R; et al. British Journal of Cancer, 1993). Based on this observation, we began treating patients with CLL and related lymphoid malignancies with a combination of Cytoxan and 2-CDA, resulting in dramatic and durable remissions.

O’Brian, Keating and other investigators at the MD Anderson then undertook this work (using fludarabine), providing for the most effective therapy for CLL in today’s literature. Unfortunately, a percentage of patients who receive this combination develop deep myelo-suppression. Therefore, the administration of this combination requires careful monitoring by the physician.

One of the most interesting aspects of the high activity observed for fludarabine was the capacity of this “anti-metabolite” to induce cell death in short term cultures of CLL cells. It was well known that CLL cells were not highly proliferative, yet the anti-metabolite class of drugs was specifically designed to stop cell proliferation at the level of DNA synthesis. We realized that 2-CDA and Fludarabine had to be killing cells, not preventing their growth. This conundrum provided an opportunity for us to test a related anti-metabolite in this disease. We chose cytarabine (Ara-C), a drug not considered effective for CLL (e.g. low proliferative rate, no likelihood of DNA synthesis inhibition, no likelihood of cytotoxicity). To our delight, low doses or Ara-C proved highly effective in controlling even the most advanced cases of CLL as we then reported.

CLL became one of our favored models for the study of human tumor biology, enabling us to study drug responses at the molecular level. Many of the observations that we made in this hematologic malignancy granted us insights that we continue to apply in solid tumors today.

Revolutionizing Treatment for Hairy Cell Leukemia Patients

Hairy cell leukemia is a rare malignancy characterized by spleen enlargement and progressive anemia and thrombocytopenia (low platelets). Bone marrow aspirations characteristically reveal a “packed marrow.” In the past, patients were often managed with splenectomy and oral chlorambucil. Response rates were low and complications, including infection and bleeding, often ensued.

The introduction of alpha interferon into the management of this disease by Gutterman and associates at M.D. Anderson, provided a meaningful advance during the 1980s. It was at this time that I was conducting a fellowship at the Scripps Clinic in La Jolla, Calif. I had the good fortune to work with Dennis Carson, MD, and his associate Bruce Wasson. They reasoned that the accumulation of deoxyadenosine, which occurred in children with Severe Combined Immunodeficiency (SCID) and was associated with the virtual annihilation of functional lymphocytes in affected patients, could be mimicked pharmacologically. By synthesizing a 2-chloro derivative of deoxyadenosine, they created 2-CDA.

Reasoning that the drug would be T-cell specific, they began early clinical trials in T-cell lymphoma patients. Dr. Carson kindly provided me with a small aliquot of 2-CDA for study in my laboratory. The activity observed in CLL, ALL and even AML, has since been confirmed. However, what was most interesting was the activity observed in the cells removed from the spleen of a hairy cell leukemia patient. The favorable dose response curve suggested to me that 2-CDA would be an active drug in this otherwise refractory malignancy. After my departure from Scripps Clinic, a junior fellow tested this response clinically, providing curative therapy in more than 90 percent of hairy cell leukemia patients. Today, a single cycle of 2-CDA is the treatment of choice for this disease, providing durable benefit in the majority of patients with minimal toxicity.

At Rational Therapeutics we continues to study novel drugs and combinations to examine their effectiveness in treating disease. Our unique ability to test malignant cells in their native state has enabled us to garner some of the most comprehensive results of any group. We will continue to identify new treatments as we move closer to finding cures for patients.