Targeted agents, combination therapies, and clinical trial equity headline Dana-Farber research

Several phase 3 studies conducted by researchers from Dana-Farber Cancer Institute show promising results for patients with multiple myeloma and breast cancer. The results of these studies, along with dozens of others led by Dana-Farber researchers, will be presented at the 2022 Annual Meeting of the American Society of Clinical Oncology (ASCO). The studies will be presented both in-person and online on June 3-7, 2022. ASCO is the world’s largest clinical cancer research meeting, attracting more than 30,000 oncology professionals from around the world.

Dana-Farber’s Paul Richardson, MD, clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center, will present results of a phase 3 study looking at a three-drug regimen (lenalidomide, bortezomib, and dexamethasone) in patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant (Abstract LBA4). The findings will be presented during ASCO’s Plenary Session on Sunday, June 5, 2022, 2:00pm-5:00pm ET. The plenary session features four studies deemed to have the greatest potential impact on patient care.

Dana-Farber’s Sara M. Tolaney, MD, MPH, Chief, Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers at Dana-Farber, is senior author on a phase 3 study in hormone receptor-positive/HER2-negative advanced breast cancer (Abstract LBA1001). The randomized clinical trial compares sacituzumab govitecan with treatment of a physician’s choice. Findings will be presented during the Breast Cancer Metastatic Oral Abstract Session on Saturday, June 4, 2022, 2:15-5:15pm ET. The study is included in the ASCO press program.

Also included in the press program is a study presented by Puja J. Umaretiya, MD, Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. The study is a retrospective look at racial, ethnic, and socioeconomic survival disparities among children with high-risk neuroblastoma (Abstract 10005). Umaretiya will present the study during the Pediatric Oncology Session on Monday, June 6, 2022, 4:00-7:00pm ET. Full press release available here.

Other key research from Dana-Farber faculty shows new treatments and diagnostic advances in brain cancer, breast cancer, Lynch Syndrome, and many others. Select studies include:

Immunotherapy drug combination is safe with promising results in glioblastoma

A novel combination of two experimental cancer immunotherapy agents along with an immune checkpoint blocker is yielding promising results in patients with newly diagnosed glioblastoma brain tumors, according to a presentation of interim, two-year follow-up clinical trial data by a Dana-Farber neuro-oncologist at the ASCO meeting.

The data from the phase I/II open-label GBM-001 trial found that “a significant percentage of patients had a robust immune response” in the peripheral blood stream and the drug combination was very well tolerated, said David Reardon, MD, clinical director of the Center for Neuro-Oncology at Dana-Farber and coordinating principal investigator of the GMB-001 clinical trial that includes 52 patients with the highly aggressive and lethal glioblastoma brain tumor.

Moreover, median survival of 17.9 months shows “modest improvement” compared to historical medians of 14 to 16-months in patients with the less-favorable unmethylated MGMT promoter status, and a median survival of 32.5 months compared to historical 23 to 25-month median survival in patients with the more-favorable methylated MGMT status. “These data are encouraging,” said Reardon, “and they highlight that combination immunotherapy for this disease may be an effective strategy where single agent immunotherapy has not worked very well. This is one of the first trials to combine a tumor vaccine strategy plus PD-1 checkpoint blockade in newly diagnosed glioblastoma patients.”

The trial is sponsored by the biotech company INOVIO which has designed two agents, or “DNA medicines” as it calls them, aimed at stimulating immune T cells in the body to target specific antigens that are highly expressed in glioblastoma tumors. These two agents, called INO-5401 and INO-9012, are given as an intramuscular injection to patients who have had surgery to remove as much tumor as possible. INO-5401 targets three glioblastoma antigens and INO-9012 is a synthetic DNA plasmid that codes for IL-12, a T cell immune activator, to help rev up the immune response against the tumor. These are given along with cemiplimab, a PD-1 inhibitor which aims to release the molecular brakes cancers use to suppress the immune response.

  • Title/Abstract: Intramuscular (IM) INO-5401 + INO-9012 with electroporation (EP) in combination with cemiplimab (REGN2810) in newly diagnosed glioblastoma (Abstract 2004)
  • Presenter: David Reardon, MD
  • Oral Abstract Session: Central Nervous System Tumors; June 6, 2022, 12:30pm-3:30pm ET

Endocrine sensitivity test predicts survival benefit of dose-dense chemotherapy for patients with HR+ breast cancer, study finds

A new genomic test designed to measure endocrine sensitivity of estrogen receptor positive breast cancer has the potential to identify patients diagnosed with ER+ breast cancer who could benefit more from dose dense chemotherapy, a regimen in which chemotherapy is administered more frequently than normal, when compared to non-dose dense regimens, research by Dana-Farber shows.

The investigators found that women with ER+ breast cancer that scores low for a biomarker called SET2,3 (i.e., indicating endocrine resistance) benefited far more from dose-dense chemotherapy than patients with higher scores. The results applied to pre- as well as postmenopausal women.

If confirmed by future studies, the biomarker could be the basis for the first test for identifying which of these patients diagnosed with ER+ breast cancer stands to have the best responses to dose-dense chemotherapy, says study presenter Otto Metzger, MD, of Dana-Farber.

The SET2,3 (sensitivity to endocrine therapy) index measures the activity of genes involved in estrogen and progesterone receptor signaling and excludes genes related to cell proliferation. A high SET2,3 score – indicates higher endocrine sensitivity, potentially deriving greater benefits from adjuvant endocrine therapy.

For the new study, researchers did SET2,3 testing on 682 tumor samples from women with ER+ breast cancer who participated in the CALGB 9471 clinical trial, which compared dose-dense chemotherapy schedules to conventional schedules. (Dose-dense treatment involves administering chemotherapy every two weeks rather than every three weeks.)

They found that patients with highly endocrine-sensitive tumors – and high SET2,3 scores – lived longer before their disease returned, and lived longer overall, than patients with less-sensitive tumors. They further found that SET2,3 was a far better indicator of patients’ prognosis than an often-used genomic test of tumor cell proliferation named PAM50.

The investigators then explored whether SET2,3 could fill the need for a test to identify patients with ER+ breast cancer who are likely to derive a greater magnitude of benefit with dose-dense chemotherapy following surgery for operable breast cancer.

The findings can be summarized as follows: SET2,3 identifies patients diagnosed with ER+ breast cancer with significantly lower chances of experiencing disease recurrence. SET2,3 outperformed PAM50 in its ability to predict patient’s outcome and in its ability to identify a subset of patients experiencing greater benefits with dose-dense chemotherapy.

Metzger says this highlights the importance of evaluating endocrine sensitivity to estimate prognosis and potentially tailor therapies for patients facing a breast cancer diagnosis.

  • Title/Abstract: Measurement of endocrine activity (SET2,3) related to prognosis and prediction of benefit from dose-dense (DD) chemotherapy in estrogen receptor-positive (ER+) cancer: CALGB 9741 (Alliance) (Abstract 505)
  • Presenter: Otto Metzger, MD
  • Oral Abstract Session: Breast Cancer – Local/Regional/Adjuvant; June 7, 2022, 10:45am-1:45pm ET

Study offers guidance for future trials of adjuvant therapy for patients with early HR+/HER2- breast cancer

To fully evaluate hormone-blocking therapy following surgery for patients with early-stage high-risk HR+/HER2- breast cancer, researchers should continue to track patients for at least five years after the completion of active treatment, according to a study reported by Dana-Farber’s Meredith Regan, ScD. The study also shows when planning post-surgical, or adjuvant, therapy for such patients, oncologists should carefully weigh the benefits and toxicities of available treatments, whether alone or in combination.

The study sought to clarify issues about the early, short-term effectiveness of drugs known as CDK4/6 inhibitors in adjuvant treatment of patients with high-risk hormone receptor-positive, HER2-negative (HR+/HER2-) breast cancer, after several clinical trials of such inhibitors in combination with endocrine therapy – drugs like tamoxifen or aromatase inhibitors, which deprive HR+ breast tumors of estrogen – have produced inconsistent early results and do not yet have long-term results available.

The monarchE trial found that combining the CDK4/6 inhibitor abemaciclib with endocrine therapy improved survival in the first two to three years after treatment, leading to abemaciclib’s approval for patients with early high-risk HR+/HER2- breast cancer. While the Penelope-B trial also showed an early treatment effect for the CDK4/6 inhibitor palbociclib plus endocrine therapy, that benefit disappeared after about four years. A third trial, dubbed PALLAS, found no survival benefit for palbociclib in combination with endocrine therapy.

To gain some perspective on these findings, Regan and her colleagues drew on data from three earlier clinical trials – BIG 1-98, TEXT, and SOFT – that compared tamoxifen and aromatase inhibitors as adjuvant therapy for patients with non-metastatic breast cancer. The trials, which collectively enrolled more than 10,000 patients, had reported results only after five years, leaving open the question of how the drugs performed in the short term, while also knowing the longer-term results.

Because the trials included patients with both high- and low-risk breast cancer, researchers extracted data specifically on high-risk patients for comparison with the trials involving CDK4/6 inhibitors. They focused on how these patients fared the first few years after treatment.

They found that with two to three years of follow-up, the benefit of endocrine therapy in the BIG 1-98, SOFT, and TEXT trials was essentially the same as that of abemaciclib plus endocrine therapy in the monarchE study. The three endocrine therapy studies showed that while the effects of treatment sometimes diminished over five years, rather than two years, they didn’t diminish nearly as much as they had over four years in the Penelope-B trial.

By focusing on the years immediately following treatment in the endocrine therapy trials, researchers gained new insights into the risk of cancer recurrence during that period. As expected, the trials showed that while the risk is relatively high in the short term, it declines steadily over the next five to ten years and persists at a low level. In each of the three trials, the pattern of risk over the first two to three years was somewhat different – something oncologists should be aware of when deciding on treatment plans with patients.

  • Title/Abstract: Historical early treatment effects of adjuvant endocrine therapy for breast cancer in high-risk subgroups: Reanalysis of BIG 1-98, SOFT and TEXT (Abstract 508)
  • Presenter: Meredith Regan, ScD
  • Oral Abstract Session: Breast Cancer – Local/Regional/Adjuvant; June 7, 2022, 10:45am-1:45pm ET

Patient-facing screening tool could increase detection of individuals with inherited cancer risk

Nearly one million people in the United States are affected by Lynch syndrome – a hereditary cancer condition with markedly elevated risk of gastrointestinal, endometrial, and other cancers. Most of them, however, are unaware of it, or find out only after they have developed cancer. A screening tool – the PREMM5 model, developed at Dana-Farber can help rapidly identify people who should undergo germline genetic testing for Lynch syndrome. PREMM5 was designed to be completed by providers but in a new project, Dana-Farber investigators adapted the screening tool as a patient-facing questionnaire and embedded the tool in the electronic health record system.

In the project led by Chinedu Ukaegbu, MBBS, MPH, new gastrointestinal cancer patients seen at Dana-Farber were able to complete the PREMM5 screener survey remotely or in clinic waiting rooms. The screener collects information about the person’s sex, age, personal history of cancer, and history of certain cancers among relatives. From these answers, a mathematical model calculates the probability that the individual has inherited any of one of the five Lynch syndrome genes. It’s recommended that anyone whose risk is 2.5% or greater be referred for genetic counseling and testing to determine if they harbor a Lynch mutation.

Between June 2020 and December 2021, 35% of new gastrointestinal cancer patients completed the screening survey, and 367 of 1,504 (24%) had a positive PREMM5 score of 2.5% or greater. As a result of their positive screen, 102 of 367 patients (28%) received a genetic counseling referral. When tested, 13 patients had cancer-related pathogenic variants, including four with Lynch syndrome. The researchers concluded that this patient-facing PREMM5 risk assessment method is feasible and identified nearly one in four general gastrointestinal oncology patients as warranting genetic evaluation. However, they noted additional refinements are needed to increase the rate of screener completion and referral for those with positive screens. Senior authors of the study are Nadine J. McCleary, MD, MPH, medical director of the Dana-Farber Patient Reported Data program, and Sapna Syngal, MD, MPH, director of gastroenterology at the Dana-Farber Brigham Cancer Center and founder of Dana-Farber’s Lynch Syndrome Center.

  • Title/Abstract: Implementing systematized patient-facing Lynch syndrome (LS) risk assessment in oncology using the electronic health record (EHR) system (Abstract 10503)
  • Presenter: Chinedu Ukaegbu, MBBS, MPH
  • Oral Abstract Session: Prevention, Risk Reduction and Hereditary Cancer; June 6, 2022, 9:00am ET

A full list of Dana-Farber Faculty Oral Presentations at the 2022 ASCO Annual Meeting is available here.

Each year ASCO also recognizes members with the Fellow of the American Society of Clinical Oncology (FASCO) distinction. This year Katherine A. Janeway, MD, MMSc, FASCO,Meredith M. Regan, ScD, FASCO, and Alexi A. Wright, MD, MPH, FASCO, are among the recipients recognized for their extraordinary volunteer service, dedication, and commitment to ASCO.

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