A clinical trial shows that a drug focused on a single genetic mutation can be effective across multiple cancer types — although blocking the mutation does not guarantee success. The drug, vemurafenib, targets the BRAF mutation and is already known to be effective in melanoma patients. In the new international trial, it appeared to work best against lung cancer and two rare disorders. The results represent the first published report from a basket study.
- Conventional clinical trials test drugs against specific cancer types.
- Basket studies focus on a tumor’s gene mutation regardless of type.
- This basket study tested a drug called vemurafenib.
- Vemurafenib was effective against several cancer types.
- Other cancers had minimal response to the drug.
A landmark study led by Memorial Sloan Kettering researchers has demonstrated the potential of precision medicine in cancer treatment. Results of an international clinical trial, published today in the New England Journal of Medicine, show that a drug focused on a single genetic mutation can be effective across multiple cancer types — although blocking the mutation does not guarantee success.
The results represent the first published report from a “basket study,” which embodies the newest approach in testing cancer therapies. While traditional clinical trials focus on a particular cancer type, basket studies are concentrated on a specific mutation found in the tumor, regardless of where the cancer originated.
“Precision medicine has come to the forefront as the future of cancer treatment,” says Physician-in-Chief José Baselga, the study’s senior author. “This is the first example of what it looks like, and proof of how it works. This study demonstrates we can design trials based on genomics as opposed to site of origin of the cancer.”
The phase II trial tested a drug called vemurafenib (Zelboraf®), which has been effective in melanoma patients whose tumors have a mutation in a gene called BRAF. The study sought to determine whether vemurafenib alone would work in patients who had other types of cancer.
The trial enrolled 122 patients from 23 centers around the world. Those in the study had a wide range of cancers, including some rare forms of the disease — but every person’s cancer carried the BRAF mutation.
Vemurafenib produced responses in a diverse set of cancers, although its effectiveness was mixed across types. The most encouraging results came in patients with non small-cell lung cancer (NSCLC), Erdheim-Chester disease, or Langerhans cell histiocytosis, the latter of which are both rare disorders. Responses were seen in 42 percent of patients with NSCLC and in 43 percent of patients with Erdheim-Chester disease and Langerhans cell histiocytosis.
In other cancers vemurafenib’s effects — at least when the drug was given alone — appeared to be minimal. Anecdotal responses were seen in some patients with colorectal, thyroid, ovarian, and salivary duct cancer, cholangiocarcinoma, clear cell sarcoma, and anaplastic pleomorphic xanthoastrocytoma.
Varying Levels of Success
“It’s encouraging that we saw responses across a wide variety of diseases,” says medical oncologist David Hyman, the study’s first author. “At the same time, these results also show that you can’t simply extrapolate from the experience in one disease to all diseases. You can’t assume a drug that works well blocking the BRAF protein in melanoma will by itself be just as effective in other cancer types with the same mutation.”
The researchers think the positive responses in NSCLC, Erdheim-Chester disease, and Langerhans cell histiocytosis could lead the FDA to approve vemurafenib as a treatment for these afflictions, which could dramatically change prospects for patients.
For the other diseases, the results can guide researchers in looking for different drug targets or developing therapies that combine vemurafenib with complementary treatments. For example, vemurafenib had no significant effect in patients with colorectal cancer, but when researchers subsequently combined it with another drug, cetuximab (ErbituxTM), some patients responded.Back to top
Benefiting Patients with Rare Cancers
Dr. Hyman explains that in addition to clarifying a treatment’s effectiveness in different tumor types, basket studies provide an important opportunity to test therapies for rare cancers, which are severely underrepresented in clinical trials. Patients with rare disorders can enroll as long as they have the mutation under study.
“Because we’re somewhat agnostic to the tumor type, these studies are more democratic in who enrolls,” he says. “That’s pretty exciting for people with rare cancers. A drug company doesn’t have to make a risky business commitment to setting up a trial — the study already exists, and patients with the mutation just enroll. So these basket studies are broadening the population of patients eligible to receive these drugs.”
Tests for the presence of BRAF and other mutations in a tumor are mainly done in patients with advanced disease. MSK tests patients’ tumors on a case-by-case basis, based on whether physicians determine that such tests will be medically useful. Patients at hospitals that don’t have the BRAF test available can ask that their tumor samples be sent to outside laboratories that are equipped to perform the tests.Back to top
Putting Discoveries into Practice
Drs. Baselga and Hyman both emphasize that basket studies are indispensible proving grounds for what actually works — or does not — after potential drug targets are found. The clinical trial reported in NEJM is merely the first in an impending wave of such studies focused on cancer-related mutations identified through the generation of huge amounts of genomic data in recent years.
“Somebody has to clinically mine this data to find out what these mutations mean in practice,” Dr. Baselga says. “We need to move from the discovery to the execution — to go to the place where the answers will be found, which is in patients.”
Since 2014, our pathologists in the Molecular Diagnostics Service have been analyzing the tumor DNA of essentially all MSK patients with advanced cancer using a powerful genomic sequencing test called MSK-IMPACTTM. The test allows doctors to detect the mutations present in tumors — information that can guide treatment choices and, in some cases, identify patients who are candidates for a basket trial.
MSK-IMPACT was developed in the Department of Pathology by genomics researcher Michael Berger. Marc Ladanyi, Chief of the Molecular Diagnostics Service, led the clinical validation of this test together with molecular pathologist Marcia Arcila, and bioinformatician Donovan Cheng. “It’s an incredibly powerful test that has enabled our physicians to extend the promise of precision medicine to many patients,” says Department of Pathology Chair David Klimstra.
Read more about MSK-IMPACT.
In 2014 MSK launched the Marie-Josée and Henry R. Kravis Center for Molecular Oncology (CMO), an ambitious initiative to improve cancer care and research through genomic analysis of patients’ tumors.
“Many people in the cancer field were saying that it would be very difficult to act on the genomic alterations that are found, that it would be hard to find enough patients to participate,” Dr. Baselga says. “But we enrolled them in record time. When we launched the CMO, that’s exactly what we saw as one of our founding principles — that we would be putting the findings to the test very soon. And already it is happening.”
Dr. Baselga says that in coming years, basket trials will increasingly test combination therapies because it is unlikely that targeting a single mutant protein will be effective. Although one drug, imatinib (Gleevec ®), has been remarkably effective in chronic myeloid leukemia patients with a mutated protein called BCR-ABL, this is unlikely to be replicated in most cancers because the disease can usually rely on an alternate biological pathway to survive if one is blocked. However, the vemurafenib study still offers reason for great optimism.
“We have no fantasies that blocking one pathway will do the trick in most cases,” Dr. Baselga explains. “But the repertoire of pathways that these tumors rely on is not endless — it’s finite. The second wave of these trials will be appropriate combinations, and this trial is a pioneer for that as well. It’s the way forward.”Back to top