The Missing Piece? Trying to Solve the Skin Cancer Puzzle

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Oncology & Biotech News

PLX4032 is an investigational treatment for metastatic melanoma, which some are calling a “miracle cure” following a 3-part article in the 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 .

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.

Florida Times-Union

Patients are also speaking out about the benefits of PLX4032. In March 2010, the 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 Jacksonville.com, at http://bit.ly/9YKOTy.)

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 15-34^th 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. Before the ECCO-ESMO Congress concluded, Plexxikon had announced it was recruiting patients for the phase II BRIM2 trial, which plans to enroll ~100 patients with advanced melanoma. The company also said it would begin accruing 700 treatment-naïve patients for the pivotal phase III BRIM3 study, which will compare PLX4032 head-to-head with dacarbazine. Like the phase I extension study, the BRIM3 and BRIM2 trials limit enrollment to patients with the BRAF mutation. Investigators for many of today’s approved targeted therapies were less discriminating in early trials and only determined the ideal target population after a drug hit the market and several patients had failed therapy. Flaherty believes that, going forward, a growing number of trials for targeted agents will use the same approach he and his colleagues have taken with PLX4032. “With so many targeted therapies moving into the clinic right now, there is strong pressure to test for the target even early on in clinical trials,” he explained.

Looking for More of the Puzzle

The downside of the PLX4032 story is that most patients who responded initially have since relapsed. “It’s not a cure,” Flaherty said, “at least not for patients with metastatic melanoma.” He expressed optimism that PLX4032 might cure some patients in the adjuvant setting. Flaherty also pointed out that the drug has been “8 years in the making”—something of a disqualifier for true miracle status.

So, PLX4032 is not a cure—at least, not yet. Given the major improvement in PFS and the strong responses seen with PLX4032, hope remains that it might constitute one piece of a cure that researchers have yet to puzzle out. To do so, they must first determine why patients relapse. “We have not nailed down the mechanism of resistance that allows tumors to progress after initially responding,” said Flaherty. “But this is the focus of numerous laboratories, as well as the clinical investigators who have been doing the trials with PLX4032.”

The researchers have only been able to collect and analyze a handful of the tumor samples, but data thus far suggest that the MAP kinase pathway where the BRAF mutation lies is somehow reactivated sometime after therapy is initiated. While they are not sure of the exact mechanism, Flaherty identified some prime suspects. “We are investigating the possibility of new BRAF mutations, activation of other components of the same pathway, or upregulation of another pathway or a parallel signaling pathway.”

Even before determining precisely why patients eventually fail on PLX4032, Flaherty would like to begin testing PLX4032 in combination with other novel agents, some of which target other mutations his patients have. He approached Roche first. Roche owns licensing rights to PLX4032. He proposed the company sponsor a trial that combined PLX4032 with another drug in its pipeline. Roche officials expressed concern that this might delay getting PLX4032 to market, and they told Flaherty this would not be in the patients’ best interest. Flaherty then pitched his idea for combination trials to GlaxoSmithKline, Novartis, Bristol-Myers Squibb, and Pfizer, finding some companies receptive enough to leave Flaherty feeling optimistic.

It is his patients’ best interests that Flaherty has in mind when proposing the combination approach. Too many of his patients die, something Flaherty would like to remedy. “We need companies to be flexible and forward-thinking about developing strategies to intercept resistance to BRAF inhibitors, as we are already facing this clinical problem.” Laboratory data from numerous sources, Flaherty said, have already shown the potential of combining certain targeted therapies, such as BRAF plus MEK inhibitors and BRAF plus PI3K inhibitors. “Some companies have drugs against each of these targets in their own portfolio—we believe that these should be prioritized for investigation now,” said Flaherty.

That does not mean he has given up on discerning why patients relapse on PLX4032. “In some respects, it is our job as NCI-funded cancer centers and investigators to work out the mechanisms of resistance to BRAF inhibitors,” Flaherty said. He believes such discoveries are inevitable and will justify investigating PLX4032 in various combinations. But those discoveries and the trials they spawn are likely to come too late for many of his patients. “The point is that the patients and we cannot delay those pursuits. We are making progress, but not as quickly as we would like,” explained Flaherty.

Flaherty has convened meetings with other experts in melanoma to discuss the issue. They already know that, for most patients, the best that PLX4032 alone can do is buy a little time; down the road, it will have to be combined with other drugs if cure remains the objective. Flaherty said academic centers simply want to accelerate the pace for this to become a clinical reality. “BRAF inhibition appears to expose a chink in the armor, but we cannot sit back and celebrate that. We have to expose it further,” he said.

The Waiting Game

Flaherty said because of the high response rate to PLX4032, phase II data might convince the FDA to accelerate approval of the drug—but those data will not be available for a minimum of 9 months. “You then have to add at least 6 months of FDA review time,” he said. According to the National Cancer Institute, survival for stage IV melanoma is 6 to 9 months from diagnosis, which means approval of PLX4032 could come too late for many people currently living with advanced melanoma.

Physicians and patients with advanced melanoma who are within reach of a center conducting a clinical trial with PLX4032 should look into enrolling, said Flaherty. “In terms of near-term control of disease, it’s fairly clear that this drug is far superior to the therapies that are available otherwise,” he said. “One could argue that the state of affairs in melanoma is sufficiently dire that clinical trials are always the priority over

administering ‘standard-of-care’ therapies for

this disease.”

The approval of PLX4032 will simply be a temporary step forward—albeit a good-sized one—if Flaherty is unable to convince at least one of the pharmaceutical companies to pursue a combination strategy using this promising drug. Patients who will be candidates for PLX4032 will then have to wait for another path to open up, with little to do but hope the process will not take longer than they have left to live.