The Missing Piece? Trying to Solve the Skin Cancer Puzzle

Christin Melton
Published: Friday, May 14, 2010
PLX4032 is an investigational treatment for metastatic melanoma, which some are calling a “miracle cure” following a 3-part article in the New York Times that discussed promising patient responses. A closer reading of the article makes it clear that PLX4032 does not cure metastatic melanoma, something Keith Flaherty, MD, a lead investigator on PLX4032, has confirmed in an interview with Oncology & Biotech News.

Flaherty is director of Developmental Therapeutics at Massachusetts General Hospital Cancer Center in Boston. He learned about PLX4032 in 2006, when he was professor of medicine at the University of Pennsylvania. Plexxikon Inc, a small drug discovery company in Berkeley, California, was developing PLX4032, a BRAF kinase inhibitor. It is highly selective for the BRAFV600E mutation, which Flaherty said approximately 50% of melanoma patients harbor. In a phase I trial, PLX4032 shrank metastatic melanoma lesions in the majority of patients and more than doubled progression-free survival (PFS) compared with standard therapies. 

Patients are also speaking out about the benefits of PLX4032. In March 2010, the Florida Times-Union of Jacksonville shared the story of Paula Heacox, who received an advanced melanoma diagnosis in 2003, at 31 years of age. After trying several different therapies that Heacox said drained her energy and her savings, in May 2009, she enrolled in a clinical trial for PLX4032 at M.D. Anderson Cancer Center in Houston, Texas. Every month, she flies to Texas so the trial investigators can assess how the treatment is working. Heacox said her tumors stopped growing almost immediately after starting PLX4032 and she no longer requires long hospitalizations. She even resumed part-time work as an accountant. (To view a videotaped interview of Heacox  about her experience, visit, at

This patient’s experience mirrors that of others who, seemingly near death’s door, partially recovered after starting PLX4032. With so few options to treat this lethal condition, it is no surprise that the success already seen with PLX4032 has inspired such optimism.


A Step Forward

Flaherty and Paul B. Chapman, MD, a colleague from Memorial Sloan-Kettering Cancer Center in New York, led the first phase I trial of PLX4032. They enrolled 55 patients in the proof-of-concept study: 49 with metastatic melanoma, 3 with thyroid cancer, 1 with rectal cancer, 1 with ovarian cancer, and 1 with a germ cell tumor. More than half the enrolled melanoma patients and all 3 thyroid cancer patients had tumors that harbored the BRAFV600E mutation. The first 26 patients received doses ranging from 100 mg of PLX4032 to 1600 mg twice daily, but responses were limited or nonexistent. Adverse effects were also minimal, and tests showed the target plasma concentration was not being reached. With the support of trial investigators, Plexxikon headed back to the laboratory to increase the bioavailability of PLX4032. The next 29 patients received the reformulated version, with much better results. Investigators set the maximum-tolerated dose at 960 mg twice daily and announced at the 2009 ASCO annual meeting that PLX4032 had demonstrated significant anticancer activity in melanoma patients whose tumors had the BRAFV600E mutation. 

PLX4032 was already generating a low-level buzz when Chapman presented results from an extension of the phase I study at the ECCO 15-34th ESMO Multidisciplinary Congress in September 2009. The study included 31 patients with metastatic melanoma, all with the targeted BRAF mutation. These patients had failed on 1 to 3 prior therapy regimens and their prognosis was poor. The overall response rate of 70% was stunning, and 25 of 27 evaluable patients experienced tumor shrinkage. In 15 patients, shrinkage exceeded 50%; 19 saw their tumors shrink by more than 30%; and 6 had tumor regression ranging from 10% to 30%. PLX4032 was well tolerated, and 97% of the observed toxicities were grade 1-2. Treatment-related adverse effects consisted mainly of rash and fatigue, but nearly one-quarter of patients developed low-grade squamous cell carcinoma. The lesions were excised and patients continued treatment with PLX4032. What generated the most excitement were the 2 complete responses, with 1 occurring after only 3 cycles of therapy with PLX4032. Although PFS was not a primary endpoint of the study, Chapman said PLX4032 appeared to stop progression for at least 6 months. Flaherty said median overall survival has still not been reached for the patients in this study. 

“By a couple of measures, it appears that PLX4032 is a big advance over available therapies [for melanoma],” Flaherty said. The response rate in BRAF-positive melanoma patients is between 70% to 80%, he said, compared with the 10% to 15% response rate seen with conventional chemotherapy or high-dose interleukin (IL)-2. “PFS also appears superior with this approach, with a median PFS of roughly 7 months for PLX4032 [compared with] 2 to 3 months for chemotherapy or high-dose IL-2,” said Flaherty. The real difference in survival between PLX4032 and standard treatment “will need to be established with a randomized trial,” he said, noting that one is already under way.

View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Medical Crossfire®: Evolving Roles for Targeted Melanoma Therapies: Assessing Rapid Progress in the Field and Looking Toward Future CombinationsFeb 28, 20191.5
Advances in™ Melanoma: Exploring BRAF/MEK in Adjuvant and Neoadjuvant SettingsSep 28, 20191.5
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