By Mikkael A. Sekeres, MD, MS

2009-12-07

The Beatles recorded the song “Come Together” 40 years ago at the request of Timothy Leary (1920-1996), who was running a dark-horse campaign for Governor of California against Ronald Reagan and whose campaign slogan was, “Come together, join the party.” Leary is best known as the psychologist who experimented with LSD as a way of promoting social interaction and raising consciousness. For those of us “leery” of illicit drugs and their consequences, luckily we have the annual ASH/ASCO Joint Symposium to satisfy our need to interact with our colleagues who treat patients with solid tumors and to raise consciousness of important advances in clinical medical oncology.

The first presentation in this year’s ASH/ASCO symposium was by Dr. Eunice Kwak of the Massachusetts General Hospital in Boston, who described a phase I dose escalation trial of PF-02341066, an oral c-Met (mesenchymal-epithelial transition factor) and ALK (anaplastic lymphoma kinase) receptor tyrosine kinase inhibitor, in patients with a variety of advanced cancers. c-Met encodes hepatocyte growth factor and is deregulated in a broad range of tumors, including cancers of the kidney, liver, stomach, breast, and brain; ALK is a fusion partner with nucleophosmin (NPM) in the t(2;5) typical of anaplastic large-cell lymphomas. Among the 37 patients enrolled in the dose-escalation part of Dr. Kwak’s study, dose-limiting toxicities included hepatotoxicity and fatigue, with the most common side effects being gastrointestinal and fatigue. Among 50 patients with ALK+ non-small cell lung cancer who were enrolled in the expanded phase II portion of the study, the overall response rate was 64 percent.

Dr. Joyce O’Shaughnessy of Baylor University in Dallas next explored the efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer (TNBC) in a phase II trial. Patients with TNBC — i.e., those whose tumors lack expression of estrogen receptors, progesterone receptors, and HER2 — have a particularly aggressive cancer that, like BRCA1-related breast cancers, is sensitive in vitro to inhibition of the cell proliferation and DNA repair enzyme PARP1. In the study described by Dr. O’Shaughnessy, 123 patients with TNBC were randomized to receive gemcitabine and carboplatin with or without BSI-201, and the two study arms were compared with respect to clinical benefit rate (CBR), progression-free survival, and overall survival. The investigators found that of 86 evaluable patients, those randomized to the arm including BSI-201 did better with respect to all outcomes, with more than a doubling of CBR and overall response rate, and significantly improved overall survival.

The other three presentations in the joint symposium focused on hematologic malignancies. Dr. Hugo Fernandez of the Moffitt Cancer Center in Tampa presented results of the E1900 Eastern Cooperative Oncology Group study of dose-intense daunorubicin (90 mg/m2) compared to standard dose (45 mg/m2) for younger adults with acute myeloid leukemia and declared that the higher dose should now be considered standard of care. Dr. Christian Gisselbrecht of Paris, France, discussed the results of the CORAL study of 396 patients with relapsed or primary refractory CD20-expressing diffuse large-cell lymphoma; the R-ICE and R-DHAP “salvage” regimens performed comparably, though R-ICE was associated with fewer adverse events. Finally, Dr. Sundar Jagannath of St. Vincent’s Medical Center in New York City discussed carfilzomib, a novel protesome inhibitor with activity in multiple myeloma patients resistant to bortezomib and other agents.

With these novel drugs and drug combinations, perhaps, as John Lennon wrote, “one and one and one is three” when it comes to future response rate possibilities in oncology.

Dr. Sekeres indicated no relevant conflicts of interest.

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