In the last decade, research into systemic therapies for cancer has transformed with more and more regimens becoming available for subsets of patients with diseases defined by histology, molecular markers, or mutations.
Aptly defined “precision medicine,” these therapeutic approaches look closely at what’s happening inside the tumor that is driving disease proliferation and progression rather than at the tumor type itself. And in some cases, therapies are becoming available in the form of disease-agnostic indications for patients whose tumors harbor a similar disease characteristic, such as a shared tumor mutation.
“This is a time of precision medicine where we are trying to identify specific molecular targets in cancer tissue and then target them for disease management.” Shilpi Gupta, MD, a medical oncologist with Atlantic Medical Group Hematology Oncology at the Morristown Medical Center, part of the Atlantic Health System in New Jersey, said in an interview with CancerNetwork®.
With this shift in approach to cancer care, investigators have become limber with their methodologies for finding targeted therapies for known molecular markers noted on tumor cells.
As such, master protocols in which multiple sub-studies evaluating 1 or more drugs and/or disease subtypes within the overall trial have become more popular in the past decade, as they allow investigators flexibility in their research to identify which treatment mechanisms show promise across tumor types, biomarkers, or genetic subtypes.
“These are trials where with fewer patients and in a shorter amount of time, we are able to identify drugs against specific targets that help us develop appropriate treatments for our patients,” Gupta said. “Unlike conventional 2-arm studies, the advantage of these trials is that we don’t need as many patients, and we get faster results.”
One such study is the phase 2 I-SPY2 trial (NCT01042379), or Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging And moLecular Analysis 2, which is examining different neoadjuvant and personalized novel treatment approaches to locally advanced breast cancer. The study is set to start enrolling patients in the Atlantic Health System in the coming months.
The term master protocol is used to broadly define trials with sub-study designs and are also referred to as basket, umbrella, or platform trials.1 According to an FDA draft guidance from 2018, agents examined in a master protocol have typically been evaluated previously and the recommended phase 2 dose (RP2D) has already been defined.
In a basket trial, a single drug regimen is tested in different patient populations defined by their disease stage, histology, number or prior treatments, biomarkers, or demographics. The primary aim of these studies are often antitumor effects, or the overall response rate, with a strong response signal potentially triggering expansion of specific sub-studies.
Multiple investigational agents or combinations may be explored in a single disease population in an umbrella trial. With umbrella trials, randomized control designs may be utilized if a common standard-of-care control is used. With new combinations, dose-finding components of sub-studies may be done if the RP2D has already been identified for each individual agent.
One notable master protocol known as the phase 2 MATCH study (NCT02465060), or Molecular Analysis for Therapy Choice, incorporates both umbrella and basket designs. In this study that is led by the National Cancer Institute in tandem with the ECOG-ACRIN Cancer Research Group, patients with cancer are assigned to a therapy according to genetic aberrations harbored by their tumors. The trial is currently enrolling arms that include therapies for patients with MET amplifications, cKIT mutations, and NTRK fusions.2 Atlantic Health Systems is also enrolling patients to MATCH at certain sites.
Platform trials are similar to umbrella trials in that they explore different treatment options against a standard-of-care control. However, by utilizing a multi-arm, multi-stage approach, different treatments can be investigated with interim analyses conducted to ensure that only promising therapies are advanced to the next stage of the trial with continued recruitment.3
Of these categories, the I-SPY2 trial is considered a platform trial in which certain therapies either “graduate” or are removed from the protocol and new agents or combinations are periodically introduced for evaluation (FIGURE).4
When asked to identify a major research finding resulting from a master protocol trial in recent years, Gupta was quick to identify 1 major contribution that came out of I-SPY2.
“Recently, the FDA approved pembrolizumab [Keytruda] in the neoadjuvant setting in the management of triple-negative breast cancer[TNBC].5 Data from KEYNOTE-522 study [NCT03036488] led to the approval of the medication,” Gupta said. “Some of the early data on the role of pembrolizumab in improving pathologic response rate in locally advanced TNBC or hormone receptor (HR) positive, HER2 negative breast cancer was noted in the ISPY2 trial”.
Gupta went on to explain that 1 key advantage of a platform trial is its unique structure that enables faster identification of potential drugs for specific tumors.
Gupta went on to explain the aims of the I-SPY2 trial and the target patient population: “This is a phase 2 neoadjuvant trial for locally advanced breast cancer where we aim to identify drugs [that] are most effective with tumor subtype and also identify early indicators of tumor response.” Discussing eligibility, Gupta said that all patients with newly diagnosed locally advanced breast cancer are eligible. The trial allows enrollment regardless of HER2, and HR status. She went on to explain how this reach may help identify treatment solutions in traditionally difficult-to-treat cohorts.
“One area of unmet need is optimization of neoadjuvant treatment options for the HR-positive patients, so that the rate of pathologic complete response is higher. With further research and drug development, we can hopefully bridge the existing gap and help our patients.”
In discussing the lead up to I-SPY2 becoming available to patients treated at one of the Atlantic Health System facilities, Gupta stressed that this and other successful trials are truly a concerted effort between investigators, multidisciplinary clinicians, and patients.
“This trial, like most trials, is a collaborative effort between the breast surgeons, radiologists, breast pathologists, and, of course, medical oncologists like me who take care of the patients. And most importantly, this is a collaboration between our patients and us. Without our patients, we would not be able to proceed with such research,” Gupta said.
But when reviewing the benefits of a trial like I-SPY2, Gupta stressed the importance of clinical research in oncology. “My hope is to always provide my patients with the best possible care, and also try to make sure that we have the latest trial options available for our patients. Here at Morristown Medical Center, Atlantic Health System, we take pride in knowing that we will be able to offer this to our patients right at their doorstep. The ultimate hope is that with trials like ISPY-2, we will be able to expand our treatment options and provide safe and effective cancer care to all our patients.”