BERLIN—An oral, selective inhibitor of the oncogenic BRAFV600E mutation showed rapid and dramatic activity in patients with metastatic melanoma in a Phase I extension study, researchers reported here at the Presidential Session of the joint Congress of the European CanCer Organisation and European Society for Medical Oncology (ECCO15-ESMO34).
While the results are early, the late-breaking presentation on the experimental agent, PLX4032, was met with enthusiasm, due to the lack of effective therapies for patients with metastatic melanoma.
In presenting the results, Paul B. Chapman, MD, Attending Physician on the Melanoma/Sarcoma Service at Memorial Sloan-Kettering Cancer Center, noted that the current median progression-free survival time for a patient with metastatic melanoma is less than two or three months, with an average survival of less than a year.
The report comes at a time of great interest in the use of targeted agents for advanced melanoma. In one recent study, for example, adding sorafenib, an oral kinase inhibitor, to dacarbazine extended progression-free survival times in patients with advanced melanoma, compared with dacarbazine alone.
Also at the ECCO-ESMO meeting, US researchers reported that the vascular endothelial growth factor inhibitor bevacizumab showed promise for the treatment of advanced melanoma patients, although it failed to improve overall survival times.
In addition, Belgium researchers reported that the tyrosine kinase inhibitor sunitinib improved outcomes in one-third of patients with advanced malignant melanoma who had failed to respond to dacarbazine-based chemotherapy.
Additionally, German researchers reported that patterns of ultrasound signals may help identify whether cancer has metastasized and whether melanoma patients need surgery.
The PLX4032 study involved 31 patients with metastatic melanoma and the BRAFV600E mutation. All were treated with the previously determined maximum tolerated dose of 960 mg of PLX4032 twice daily.
The BRAF mutation is implicated in about 50% of melanomas and 5% of colorectal cancers.
Among the 27 evaluable patients, the overall response rate was 70%, with two patients having complete responses.
The results are “unprecedented,” Dr. Chapman said.
Chemotherapy agents currently used to treat advanced melanoma are associated with an overall response rate of about 15%.
Showing PET scan images from several patients taken at baseline and Day 15, Dr. Chapman said, “This one clearly shows the tumor isn't taking up glucose anymore at two weeks.” And turning to another patient's scans, Dr. Chapman pointed to signs of recalcification at two weeks. “We began to see signs of tumors turning off within two weeks. I've never seen anything like it.
“Responses have been seen in subcutaneous sites, liver, lung, GI, and bone, and have been associated with resolution of symptoms,” he added.
Secondary Cancer Risk
The median age of the patients, 61% of whom were male, was 52; 39% had failed to respond to three or more previous therapies.
Grade 3 adverse effects reported to date are fatigue, arthralgias, photosensitivity, rash, and elevated alkaline phosphatase.
“About 40% of patients had a drug holiday or dose reduction, after which the problems resolved,” Dr. Chapman said. No patient discontinued therapy at the 960-mg dose due to side effects.
Also, 23% of patients developed squamous cell carcinoma of the skin, but it was easily resolved by excision, Dr. Chapman said. “It's important to screen patients taking PLX403.”
Giving some background, Chris Twelves, MD, Co-chairman of the meeting's Program Committee and Professor of Clinical Cancer Pharmacology at Leeds Institute of Molecular Medicine in the UK, said, “It's important to note that they are not swapping out one cancer for another. Melanoma, once it spreads, is almost always lethal. Squamous cell cancers are local and easily treatable.”
ECCO President: ‘Spectacular’
And ECCO President Alexander Eggermont, MD, called the results “simply spectacular,” predicting that the drug “will transform melanoma work into a very exciting field instead of a graveyard.”
Of note, he said, is that earlier research showed that patients who did not have a mutated BRAF gene did not respond to the drug. In the patients, the progression-free survival time was less than two months.
“It's a targeted drug that makes sense. We know exactly what we are targeting, that is what all the excitement is about,” said Dr. Eggermont, Head of Surgical Oncology at Erasmus University Medical Center in Rotterdam.
Echoed Dr. Twelves: “Results like this have never been seen in metastatic melanoma.”
Dr. Chapman and colleagues are now planning a study of 90 patients beginning at the end of this year and a larger international trial involving several hundred patients starting early next year.
Plexicon, which makes the new drug and has licensed it to Roche, funded the work.
Also at the meeting, researchers reported that bevacizumab failed to improve overall survival times in advanced melanoma patients when added to carboplatin and paclitaxel.
Results of the randomized, multicenter Phase II trial, also funded by Roche, were presented by Steven J. O'Day, MD, Chief of Research and Director of the Melanoma Program at the Angeles Clinic and Research Institute in Los Angeles.
The BEAM (A Study of Bevacizumab with Carboplatin and Paclitaxel Chemotherapy for the First-Line Treatment of Patients with Metastatic Melanoma) trial involved 214 patients with previously untreated, Stage IV, M1a/b and M1c melanoma. The patients were randomized in a two-to-one fashion to receive chemotherapy with or without bevacizumab.
An analysis performed when the researchers submitted a written abstract to ECCO15-ESMO34 showed a median progression-free survival time of 5.6 months for the bevacizumab arm vs 4.2 months for the chemotherapy-alone arm.
This corresponded to a 22% improvement in favor of bevacizumab, but did not reach statistical significance.
The preliminary data also showed a median overall survival of 12.3 months in the bevacizumab arm vs 8.6 months with chemotherapy alone. This translated to a 33% reduction in the hazard ratio in favor of the VEGF inhibitor that was statistically significant.
However, a follow-up analysis performed in the week before Dr. O'Day's late-breaking presentation showed that the overall survival time in the control arm had increased to 9.2 months, resulting in a nonsignificant hazard benefit of 21%.
The addition of the bevacizumab (Avastin) to chemotherapy was well tolerated and caused no new or unexpected safety issues, he reported.
Further Study Called For
Dr. O'Day blamed the lack of significance on the fact that overall survival times were a secondary endpoint and that the study wasn't powered to look at survival. “This happens in smaller studies,” he said.
As a result, Dr. O'Day said, he remains enthusiastic about the drug's promise for a cancer that has few therapeutic options.
“We saw consistent trends toward improved outcomes, with about a 20% improvement in all endpoints. There are also data showing that angiogenesis is a pivotal part of melanoma, and we have seen Avastin improve survival in other cancers driven by angiogenesis.
“Hopefully these results will prompt a Phase III trial,” he said. “Roche is currently in the process of making a decision.”
Dr. Twelves agreed that the drug warranted further investigation in the treatment of metastatic melanoma. “The first study of Avastin in breast cancer failed to meet its endpoint, and then in future trials it worked,” he said.
Dr. Eggermont said that to be effective in metastatic melanoma, a drug needs to improve overall survival times. “In the last few randomized controlled trials, single and drug combinations all failed to impact overall survival. A few of them had an impact on progression-free survival, so progression-free survival in melanoma is not a very good endpoint,” he said.
The Phase II study of sunitinib involved 21 patients with locally advanced or metastatic melanoma who had failed to respond to at least one line of dacarbazine-based chemotherapy.
The patients received treatment with sunitinib in six weekly cycles, with 50 mg once-daily dosing for four consecutive weeks, followed by a two-week off-treatment period.
Three patients discontinued the drug due to adverse events, with one case each of cardiac insufficiency, cerebral hemorraghia, and inability to swallow the medication.
Of the 18 evaluable patients, two patients (11%) had partial responses, with a mean duration of 5.4 months. Five patients (28%) had stable disease, with a mean duration of 4.4 months, and 11 (61%) had progressive disease.
The most frequent toxicities were asthenia (62%), anorexia (33%), and nausea (43%). No Grade 4 toxicities were observed.
Recruitment into the second stage of the study, in which angiogenic biomarkers are being correlated with clinical activity, is now ongoing, the researchers said.
Another, prospective study presented at the Congress showed that patterns of ultrasound signals may help identify whether cancer has metastasized, and to what extent.
The test may also help oncologists to decide whether surgery is indicated, said Christiane Voit, MD, PhD, Head of the Diagnostic Unit at the Skin Cancer Center at Humboldt University in Berlin.
“We have identified two ultrasound patterns of lymph node metastasis in melanoma patients, which can identify correctly any amount of tumor cells in the sentinel lymph nodes in 75% to 90% of cases before proceeding to surgery on the sentinel lymph nodes. Ultrasound patterns correlated with disease progression, tumor burden, survival, and prognosis.”
In the first 400 of 850 patients with Stage I or II melanoma studied, the combined use of the two ultrasound patterns correctly identified the amount of cancer cells in the lymph nodes in 80% of cases.
In 83% of cases, a balloon-shaped ultrasound pattern with or without loss of central echoes correlated with of a large amount of cancer cells in the sentinel node. The pattern occurred only in cases of advanced metastasis, Dr. Voit said.
A pattern of peripheral perfusion, with small blood vessels surrounding the lymph node, was an early sign of a small number of cancer cells.
The study also showed that 93% of patients with neither ultrasound pattern, 87% of patients with the peripheral perfusion pattern, and 56% with the balloon-shaped pattern survived for five or more years.
“For the first time, we have established that ultrasound patterns can be used as criteria for diagnosing disease progression and tumor burden as well as survival,” Dr. Voit said.
They need to be confirmed in prospective randomized clinical trials, she said, but could lead to a strategy for sparing patients from unnecessary surgery.