The more we learn more about the underlying mutations that drive cancer the better we get at more precisely hitting those targets with specialized, less toxic treatments. We now understand that a one-size-fits all approach to treating cancer is ineffective for many patients. As The 62nd American Society of Hematology (ASH) annual Meeting ends, let’s take a look at results from studies of targeted therapies that work by interfering with the altered genes that cause cancer cells to grow and spread. Much of the work stems from research supported by LLS.
Precision Medicine in Acute Myeloid Leukemia
More than four years ago, LLS launched its Beat AML Master Clinical Trial, a precision medicine study that uses genomic technology to identify a patient’s subtype of acute myeloid leukemia (AML) and matches them with a targeted therapy in one of the Beat AML sub-studies. Eytan Stein, MD, of Memorial Sloan Kettering Cancer Center, presented data from one of those sub-studies on Monday showing that enasidenib is a highly effective drug in newly diagnosed older AML patients with the IDH2 mutation. IDH1 and IDH2 mutations make up about 20 percent of AML patients. Stein said that 47 percent of the patients in the study had a complete response to enasidenib, and the median overall survival was 24.4 months (half the patients were still alive after more than two years).
Patients who did not respond to enasidenib alone were given the drug combined with another drug, azacitidine, whichswitches on a tumor-suppressing gene. Seven out of 17, or 41 percent, of those patients achieved a complete response. Dr. Stein said Beat AML will test enasidenib with other novel agents in patients who are resistant to the drug on its own. The FDA approved enasidenib in 2017 for IDH2-positive AML patients who have relapsed or don’t respond to previous treatment; it is being tested in Beat AML as a first-line treatment for newly diagnosed patients. A recent publication about the Beat AML study in Nature Medicine showed that patients in the study generally did better than those who opted for standard treatment.
More than three years after the first chimeric antigen receptor (CAR) T-cell therapy achieved U.S. Food and Drug Administration (FDA) approval, the revolutionary approach that has upended blood cancer treatment continues to generate excitement.
LLS support over more than two decades helped lay the groundwork for this approach to therapy that has been a game-changer for patients who have relapsed multiple times and seemingly exhausted their treatment options. The method works by infusing immune (T) cells with cancer-attacking synthetic receptors that seek out and bind to a specific protein on the surface of the cancer cells, causing their destruction. The CAR-T cells continue to expand and fight the cancer cells, becoming a living drug within the patient’s body. Pediatric acute lymphoblastic leukemia patients and adults with large B-cell lymphomas have benefited from long-lasting remissions from the first CAR-Ts approved. The latest CAR-T approval was in August for patients with mantle cell lymphoma.
Consensus is building that the next CAR-Ts on the horizon will be for multiple myeloma patients and follicular lymphoma and marginal zone lymphoma patients who have relapsed multiple times. During this week’s virtual 62nd American Society of Hematology (ASH) annual meeting, a slew of presentations makes clear several of these are likely to get approved in early 2021.
The myeloma CAR-Ts all target a protein called BCMA found on cancerous plasma cells in myeloma patients. BCMA has emerged as a prime target for myeloma treatment, and the first BCMA-targeting therapy, an antibody-drug conjugate (an antibody bound to a cytotoxic agent), was approved by the FDA in August – read more here.
Of the multiple companies vying in the BCMA-targeting CAR-T space, Johnson & Johnson’s product, ciltacabtagene autoleucel (cilta-cel), appears to be the frontrunner, with the highest response rates and longest-lasting CAR-T cells. In a study of 97 patients, 97 percent responded to the treatment, and 67 percent had a complete response, meaning no cancer cells were detectable. At just over one year (the median follow-up, meaning at least 50 percent of the patients had been on the trial), 77 percent of the patients were still alive and their cancer had not gotten worse.
Johnson & Johnson plans to submit its data to the FDA within the next few weeks. What's more, Bristol Myers Squibb/Bluebird’s idecabtagene vicleucel (ide-cel) – also promising while not as long-lasting in trials to date – is already before the FDA with a decision anticipated in March. While not involved in the study present at the ASH meeting, an LLS-funded researcher at Emory University, Madhav Dhokapkar, MBBS, is studying this therapy to find ways to make it more durable, safer, and more effective. Many CAR-T products from Chinese companies were also presented at the meeting.
The length of time that BCMA-targeting CAR-T cells can last in patients has been questionable, so the results presented at this ASH meeting are encouraging. At the same time, the deaths of several patients on trials have raised concerns about potential toxicities, including dangerous neurological side effects and another extreme immune response called cytokine release syndrome. Despite this, the FDA might determine that the benefits for patients without other treatment options outweigh the risks.
Patients with follicular (FL) and marginal zone lymphoma (MZL), two slow-moving “indolent” forms of non-Hodgkin lymphoma, also have reason for hope. Results from a clinical trial entitled ZUMA-5, testing a CAR-T developed by Kite Pharma, a Gilead company, showed high response rates for patients with both forms of the disease. LLS helped Kite Pharma launch their CAR-T program through a partnership entered in 2015.
Of 104 patients evaluated, 84 with FL and 20 with MZL, 92 percent had an objective response, meaning their cancer cells were reduced; 76 percent of patients had a complete response, meaning the cancer became undetectable after a median follow-up of 17.5 months (the time when 50 percent of the patients have been on trial).
Researchers across the globe – with support from LLS – continue to work tirelessly to usher in the next generation of CAR T-cell therapies so that they're safer and more efficacious for more patients with blood cancers.
With the COVID-19 pandemic driving yet another science conference to the virtual world, it is fitting that the 62nd ASH Annual Meeting and Exposition officially kicked off today with a virtual fireside chat via live stream featuring none other than Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, and a member of the administration’s coronavirus task force.
The ASH meeting typically fills massive convention centers each December. Each year, 40,000 scientists, clinicians and other healthcare professionals, pharmaceutical and biotechnology executives, media, and communications specialists, gather to share and learn about the latest advances in the blood cancers and other blood diseases, including sick cell anemia and hemophilia
Dr. Fauci and ASH president Stephanie Lee, MD, discussed the impact of COVID-19 on patients with blood cancers. Despite cancer patients being excluded from clinical trials for impending COVID-19 vaccines, Dr. Fauci recommended that patients who are immunocompromised, including blood cancer patients, receive the vaccine when it becomes available. He also said that all healthy people should get the vaccine to create the umbrella effect of herd immunity. Dr. Fauci also said that “we can crush the virus” if billions of people around the globe have access to the vaccine. In the meantime, he stressed it is urgent to continue to practice responsible public health measures like wearing masks and social distancing.
