ARTEMIS clinical trial offers triple-negative patients personalized therapy

Triple-negative breast cancer (TNBC) makes up 15 to 20 percent of breast cancer diagnoses. The condition often is considered a single disease, when in reality, TNBC is a catch-all diagnosis of biologically different breast cancer subtypes that lack expression of estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor receptor 2 (HER2).

In patients with localized disease, a neoadjuvant chemotherapy regimen of Adriamycin (doxorubicin) and cyclophosphamide (AC) followed by a taxane-based regimen results in a pathologic complete response in 35 to 40 percent of patients and is associated with an excellent long-term prognosis.

“Over half of patients have a tumor that’s insensitive to chemotherapy, which is manifested as residual disease identified at the time of surgery,” says Stacy Moulder, M.D., professor of Breast Medical Oncology. “And 50 to 60 percent of that population will experience a recurrence of their cancer within two to three years.”  

Thanks to MD Anderson’s Breast Cancer Moon Shot™, which is co-led by Moulder, and the ARTEMIS clinical trial, there’s new focus on trying to:

• understand why some TNBC cases are chemotherapy sensitive (respond to chemotherapy)
• discover targeted therapies for patients whose disease is not chemotherapy sensitive

The Breast Cancer Moon Shot is part of MD Anderson’s Moon Shots Program™, a collaborative effort to accelerate the pace at which scientific discoveries are translated into clinical advances that save patients’ lives.

Personalizing triple-negative breast cancer treatment

“ARTEMIS is one of the very few trials ― and probably the first ― trying to identify chemotherapy-insensitive triple-negative tumors during AC neoadjuvant therapy, and then switching patients to a targeted therapy regimen that’s based on their molecular profiling,” says Moulder, principal investigator on the trial.

Traditionally, neoadjuvant studies treat all enrolled patients with targeted therapy that’s not specific to their triple-negative subtype, resulting in up to half of patients with chemotherapy-sensitive disease receiving an unnecessary targeted therapy, as well as the toxicities that come with it.

“What we’re doing that’s unique is identifying the chemotherapy-insensitive population first, and then focusing our efforts with subtype-selected targeted therapy there,” Moulder says.

Molecular profiling offers guidance

The goal of ARTEMIS is to find out if treating chemotherapy-insensitive TNBC patients with targeted therapy that has been selected based on subtyping will result in higher rates of pathologic complete response and better long-term survival compared with standard chemotherapy. To answer this, patients in the study undergo biopsy before treatment, and then immediately begin neoadjuvant AC while their TNBC subtype is determined through molecular testing. Response is assessed by imaging after two cycles and at completion of four cycles of AC chemotherapy. If a patient’s disease is deemed chemotherapy insensitive based on imaging during or after chemotherapy, the patient is offered the opportunity to participate in a non-randomized, single-arm therapeutic Phase II clinical trial that’s selected based on the TNBC subtype.  

In addition to pretreatment biopsies, tissue is harvested by biopsy after chemotherapy and at the time of completion of neoadjuvant therapy (surgical resection) in order to provide material for translational research that aims to identify mechanisms of chemotherapy resistance. The genomic profiling efforts, including RNA sequencing and whole-exome sequencing, are supported by the Cancer Genomics Laboratory, a platform of the Moon Shots Program.

Another platform, Adaptive Patient-Oriented Longitudinal Learning and Optimization (APOLLO), is conducting immune-correlative analysis by staining tumors to see if changes in the tumors’ immune cells make a difference in how patients respond to treatment.

“We’re looking at the chemotherapy-sensitive tumors and comparing them with the resistant tumors to determine if there are potential targets that we haven’t ever considered, based on what we’re seeing at each biopsy time point,” Moulder says.

Unique design eliminates delay in treatment

Because of the resources from the Moon Shots Program, as well as the trial’s unique design, patients who enroll in ARTEMIS typically undergo a biopsy within two to three days of consenting for the trial, and start chemotherapy immediately.

“One of the beauties of this trial is that the patient doesn’t have to wait for the result of the molecular profiling to start treatment,” Moulder says. “The patient can start therapy, and by the time we need to make a decision after the first phase of treatment, we have that information to decide next steps.”

If a patient’s tumor is chemotherapy sensitive, she will continue with the AC chemotherapy, but if the tumor is chemotherapy insensitive, the patient is offered the opportunity to participate in one of the following four non-randomized, single-arm therapeutic clinical trials linked to ARTEMIS:

• Study #2015-0488 combines chemotherapy with a drug that blocks the androgen receptor, which is present in 15 to 20 percent of all TNBC.
• Study #2015-0087 is exploring the combination of a VEGFr inhibitor, an mTOR inhibitor and chemotherapy.
• Study #2015-0294 combines chemotherapy and an EGFR monoclonal antibody.
• Study #2014-1043 combines chemotherapy with a PD-L1 inhibitor in patients who have evidence of lymphocytic infiltration into the tumor.

With the information found by the tumor analysis, patients are offered the therapeutic trial best suited for their disease.

“We’re guiding patients into a clinical trial more thoughtfully, rather than treating everyone’s triple-negative disease the same,” Moulder says.

Working hand-in-hand with community physicians

Moulder and her team see the ARTEMIS trial as an opportunity to partner with medical oncologists in the communities where patients live, providing them comfort and convenience.

“After genomic profiling, we send patients back to their community medical oncologists to receive treatment,” Moulder says. “We feel like it’s great for patients to be in their home environment, where it’s easier to receive chemotherapy.”

However, for patients whose tumor doesn’t have a robust response to chemotherapy, MD Anderson can offer a second opportunity for treatment with the portfolio of clinical trials linked to ARTEMIS.

Promising outlooks, but more patients needed

In an initial analysis of a cohort of patients who were deemed chemotherapy insensitive by ultrasound (less than 50 percent volumetric reduction after four cycles of AC or progression during AC), none of the patients who received standard chemotherapy and a taxane as the second phase of neoadjuvant therapy had a pathologic complete response. However, of those patients in the insensitive cohort who  enrolled in one of the four therapeutic trials linked to ARTEMIS and received targeted therapy, 15 percent had a pathologic complete response.

“It’s a good indication that we’re able to save some of these patients with targeted therapy,” Moulder says. “But we need more patients to see if that change will actually maintain over a larger group of patients, and if that will be statistically significant in a larger cohort.”