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The future of BRAF inhibitors

Recent research from Jennifer Wargo’s laboratory suggests that mutated BRAF helps melanomas hide from the immune system (top). BRAF inhibitors allow the cells to express surface proteins, which make the tumors susceptible to destruction by the immune system (bottom). Courtesy Jennifer Wargo

It is daunting for even the most dedicated of scholars to track the alphabet soup of promising molecular targets and pathways. But last year a BRAF mutation joined the handful of oncogenes that can be therapeutically targeted by a selective inhibitor. Researchers reported a striking regression of metastatic melanoma tumors.

“A major breakthrough,” said an editorial in the New England Journal of Medicine (NEJM). The editorial, “Melanoma—An Unlikely Poster Child for Personalized Cancer Therapy,” was published in August alongside the phase I results of one of the experimental inhibitors (RG7204/PLX4032, Roche) by Keith Flaherty, MD (MGH) and his co-investigators.

In the trial, 81 percent of the 32 patients in the extension cohort (whose cancers carried the signature BRAF mutation) saw a temporary reversal of their metastatic melanomas. On radiology scans, lesions that had spread to the bone, liver, and lung seemed to disappear within weeks of the first dose. Then, in an unpredictable two to 20 months later, the cancers somehow bypassed the single inhibitor and roared back. A front-page series in the New York Times detailed the rollercoaster rides of individuals in the phase I study.

Old news, new directions

Despite key details about survival yet to be reported, BRAF feels like old news to many researchers closest to the science. Flaherty expects FDA approval by summer for the Roche BRAF inhibitor for metastatic melanoma. “It is now clear that treatment of patients with metastatic melanoma tumors harboring a BRAF mutation results in profound tumor regression and symptom improvement in the majority of patients,” he wrote last year in an overview of an international melanoma research meeting.

Subsequent trials of the Roche drug and of a selective BRAF inhibitor from GlaxoSmithKline (GSK2118436) are expected to show similar potent short-term effects in tumor regression. A phase III multicenter randomized trial headed by Flaherty accrued its last patient in December. He and his co-investigators will present the first details of the phase III results at the June meeting of the American Society of Clinical Oncology (ASCO) in Chicago, but already a Roche news release in January declared both an overall survival and a progression-free survival benefit, compared to dacarbazine, the standard chemotherapy.

So far, “we don’t have the clear sense that we have cured anyone” with the BRAF inhibitor, Flaherty said. In fact, if approved by federal regulators, the first clinical use of BRAF inhibitors probably will be in palliative treatment of people with metastatic melanomas with BRAF mutations.

Formal peer-reviewed papers that rigorously analyze the data from the clinical trials may take several more months. But researchers at DF/HCC and elsewhere observed resistance developing as soon as two months into the early phase clinical trials, and have been searching for answers and rationales for the next round of studies designed to build upon the BRAF inhibitors. “We seek to understand the implications of our first generation of targeted therapies,” said Flaherty. “We’re moving ahead in multiple directions.”

Many questions, many patients

DF/HCC researchers are optimistic about testing BRAF inhibitors in combination with other selective inhibitors within or across molecular pathways. They have some basic questions: What is the tumor doing at the genetic level to bypass BRAF inhibition? What is keeping alive the fraction of tumors that are not dying? Can the new targeted combinations be given safely?

They also want to test BRAF with other therapies that could buy more time for patients, such as surgery, immunotherapy, antiangiogenesis, and cell cycle regulation. They’re exploring strategies to take out tumor cells that survive the BRAF inhibitor, as well as pairing BRAF inhibitors as adjuvant therapy with surgery to try to reduce recurrence of early stage melanoma. Other avenues of study test BRAF inhibitors alone or in combination therapies against other cancers. And researchers are alert for evidence of effective targets in the half of all melanomas that do not harbor a BRAF mutation.

The findings from these widespread efforts will have significant public health implications. The handful of targeted anticancer agents approved so far affect rare cancers of the blood and stomach or a small proportion of lung cancer tumors. BRAF mutations touch the largest potential pool of cancer patients yet in the arena of targeted molecular therapy—about half of all melanomas and about eight percent of other cancers, including colon and thyroid, for which the BRAF inhibitors are in early clinical testing.

Recovery, resistance, reinvention

The biggest problem with inhibiting BRAF was predicted even before investigators observed their first hopeful reprieves and disappointing relapses two years ago: drug resistance.  Researchers had observed the same thing with earlier selective inhibitors. Tumors reduced by the targeted agents soon grew back, including chronic myelogenous leukemia (imatinib to inhibit abl), gastrointestinal stromal tumors (imatinib against activating mutations in KIT and ABL1 oncogenes), non-small-cell lung cancer (erlotinib for EGFR), and breast cancer (trastuzumab or lapatinib targeting HER2/neu gene amplification).

Almost as soon as the BRAF clinical trials began, scientists were back in the lab working on strategies to circumvent the resistance problem. The molecular biology of BRAF-mutant melanomas has been worked out in enough detail to direct the next steps in clinical research. “In some ways, we’re benefiting from being fifth in line,” Flaherty said. “This is happening when there has been an explosion of other drugs and strategies. There are multiple rational directions that haven’t existed in other cancers.”

Flaherty predicts researchers will be building two-drug combinations with BRAF this year and next. “In 2013, we may look at three-drug combinations,” he said.

First up: BRAF/MEK

The first dually targeted clinical study tests the inhibitors of mutant BRAF and its constituently overactivated downstream partner MEK (GSK2118436 and GSK1120212, GlaxoSmithKline). The study has advanced to phase II. Flaherty will present preliminary phase I results at the June ASCO meeting.

Researchers in the field have argued that adding MEK could help fight drug resistance to BRAF inhibition. In supportive evidence, Levi Garraway, MD, PhD (DFCI) and his colleagues recently reported that two likely resistance pathways bypassed BRAF and converged on MEK. Scientists also speculate that MEK inhibition could block a frequent side effect of BRAF inhibition in the Roche trials, the complication of low-grade squamous-cell carcinomas forming from normal tissue in about one-third of study participants. The localized carcinomas have been successfully excised with no apparent malignancy.

Other points of intervention upstream or downstream of BRAF in the MAP kinase pathway are under preclinical investigation and development.

Flaherty and his colleagues also want to test other BRAF inhibitors with promising targeted agents of other molecular pathways, if warranted by a tumor’s genetic signature. For example, errant signaling through the PI3K pathway (including AKT, mTOR, and PTEN) may fuel tumor growth, although the pathway may not be as critical an oncogenic driver in melanoma as it is in breast, colon, and other cancers. Flaherty wants to test the leading candidates with a BRAF inhibitor as they emerge from early phase clinical testing.

Harnessing the immune system

Genetic alterations nominate certain targets, Flaherty said, but there is a limit to the number of genetic alterations that can be targeted with drugs. In a novel pairing of strategies, the team is planning to combine BRAF inhibitors with immunotherapy.

Immunotherapy is one of the standard treatments for metastatic melanoma. Two agents were recently approved by the FDA. High-dose interleukin 2 (IL2) can result in cures lasting more than five years in about seven percent of people, but is rarely used because of the special expertise need to manage the considerable toxicities. Ipilimumab, which blocks an immune system brake and keeps T cells activated, also shows evidence of survival benefits in people with melanoma. In a phase III study by Stephen Hodi, MD (DFCI) and his co-authors in August in NEJM, ipilimumab boosted immune action against cancer cells for a significant antitumor effect. The therapy was approved by the FDA in late March for late-stage melanoma.

An emerging rationale for pairing immunotherapy with a BRAF inhibitor is building in the laboratory of Jennifer Wargo, MD (MGH). In preliminary experiments, she and her team reported that melanoma cell lines treated with a BRAF inhibitor expressed more surface tumor antigens that T cells could recognize. In July, she and her colleagues reported in Cancer Research that human melanoma cells treated with BRAF inhibitors were more sensitive to the immune system through this upregulation of antigenic proteins on the cell surface. They hypothesize that the BRAF mutation itself gives melanomas the ability to evade the immune system by reducing the number of tumor antigens on their surface and that treatment with a BRAF inhibitor reverses this effect (see illustration).

In a cautionary note for combinatorial strategies, they found that a similar strategy, MEK inhibition, can also restore antigen expression to melanoma cells, but MEK inhibitors suppress immune function. “We haven’t proven it in patient samples,” she said, “but it’s a concern.”

In follow-up work on tumor samples from patients treated with BRAF inhibitors, she sees as much as a 100-fold increase in surface tumor antigens, as well as other evidence that the immune system is mediating the response. She speculates that BRAF inhibitors could be working through the immune system to kill melanoma cells. If so, “then immunotherapy should be able to kill more tumor cells up front, which may translate into more durable responses in patients with melanoma,” says Wargo, who will present her findings at the April American Association for Cancer Research meeting in Orlando.

Wargo is planning two combination immunotherapy trials in collaboration with Hodi and others, one adding ipilimumab to the BRAF inhibitor. The other one, likely to begin this year, will test a combination strategy using IL2 with a BRAF inhibitor.

Other combinatorial efforts

Half of all melanomas may share the BRAF mutation, but BRAF mutant melanomas have many different genetic mutations that can derail the machinery that prevents cells from dividing out of control. Another candidate on Flaherty’s list of combinations to try with BRAF is an inhibitor of cdk4, part of a cell cycle complex that malfunctions in cancer.

In yet another strategy, Flaherty is working with Michael Atkins, MD (BIDMC) to test whether the antiangiogenic drug Avastin (bevacizumab) and a BRAF inhibitor can enhance the other drug’s effects. This trial is likely to begin this year.

The early single BRAF inhibitor trials were so impressive that a September article in the New York Times series questioned whether it was ethical to randomize such desperately ill patients to a study arm of the marginally effective standard chemotherapy. Justification comes in part from expense of new treatments ($4,000 to $8,000 a month for single targeted therapies) and the evidence for making health policy decisions on behalf of large populations, argued an opinion piece in NEJM in February co-authored by Steven Joffe, MD, MPH (DFCI). Flaherty and his colleagues are keeping those large populations in mind as they work toward the next generation of strategies to understand and block the routes melanoma uses to bypass such an initially effective therapy.

 — Carol Cruzan Morton