Matchmakers: How Basket Trials Match Patients With Drugs Based on Their Tumors

Drew Huggins was running out of options. After his diagnosis of metastatic pancreatic cancer two years ago, at age 47, he hadn’t had any luck with the treatments he’d tried so far.

His tumors didn’t respond to 13 cycles of FOLFIRINOX, an arduous four-drug chemotherapy combination. The chemo- therapy combination of gemcitabine and paclitaxel didn’t work either. They only left him with severe neuropathy, which causes debilitating pain, weakness and numbness in his hands and feet, from which he is still trying to recover. Next, he enrolled in a clinical trial at The University of Texas MD Anderson Cancer Center in Houston that used an antibody-drug conjugate to try to attack the tumor. But while Huggins was on this drug, the tumor grew by 25%.

“After that, I pushed and said, ‘There’s got to be something else that can be done here,’” Huggins recalls.

It’s rare for pancreatic tumors to have a genetic mutation that drugs can target. But Huggins’ oncologist took a “we’ll never know till we try” approach, and it paid off. The doctor sent tissue from one of Huggins’ tumors to a lab to see if it had any gene mutations that might be vulnerable to existing targeted drugs.

“And that’s when it came back with the match,” Huggins says.

Huggins’ tumor had a rare mutation called an NRG1 fusion. This genetic change happens in only about 1.5% of pancreatic cancers, according to some estimates. That gives NRG1-driven pancreatic cancers the distinction of being a “rare disease.” The gene fusion made Huggins eligible for a phase 1 clinical trial in MD Anderson’s Department of Investigational Cancer Therapeutics. The trial tests a targeted drug called Zeno (zenocutuzumab) in any type of cancer driven by NRG1 fusions.

Huggins travels the 200-plus miles from his home in San Antonio, Texas, to MD Anderson for two-hour infusions every two weeks. His first scan six weeks into the experimental treatment showed a significant reduction in tumor size.

“It was dramatic. On the scans, you could see the difference in the dark areas and the areas where it was cleared up,” Huggins says.

Now, nine months later and still on the treatment, his cancer is stable.

Increasingly, researchers are playing matchmaker between patients with metastatic cancer and targeted drugs. In studies called basket trials, researchers focus less on the cancer site — such as the breast, lung or colon — and more on the genetic makeup of the tumor no matter where it first appeared. They perform comprehensive genetic analysis of the tumor tissue to see if it carries any tumor-driving mutations for which targeted drugs already exist. The existing drug may not be approved by the Food and Drug Administration (FDA) or may have approval to treat only a certain type of cancer with that particular mutation. But in the trial, anyone with that mutation, regardless of the type of cancer, receives treatment with that drug to see if it might work for them.

“Is treatment response guided more by the mutation or more by the tumor type? We are looking for the answer to that. The results may be complicated,” says Dr. Peter O’Dwyer, who co-chairs the NCI-MATCH trial, the largest-ever basket trial. The publicly funded trial is co-led by the ECOG-ACRIN Cancer Research Group and the NCI.

While basket trials won’t lead to effective new treatment options for everyone, the study design is bringing hope as well as life-prolonging treatment to many people who previously had none.

What Are Targeted Drugs?

Targeted drugs, also known as precision treatments, attack a specific genetic characteristic of the tumor that is helping it grow. The drugs act more specifically on cancer cells, unlike chemotherapy, which attacks cancerous and normal cells. Typically, a specific genetic alteration or presence of a protein in the tumor would be necessary to be eligible for treatment.

Among FDA-approved targeted drugs are treatments for breast, colorectal, skin and lung cancers and many others. Typically, the FDA approves these drugs to treat a specific type of cancer, such as lung. Sometimes drugs earn approval for another type of cancer later, after additional studies prove it is beneficial for that other type.

Non-small cell lung cancer is one in which targeted drugs have been a major advance. There are nearly a dozen targetable gene mutations that arise in this type of cancer. Comprehensive biomarker testing matches patients or the genetic makeup of their unique tumor with treatments.

This type of genetic matchmaking is why Shyreece Pompey, 50, who now lives in Woodland, California, believes she’s alive today. She has been living with stage 4 non-small cell lung cancer for seven years.

When she was diagnosed with advanced cancer at a local community hospital in St. Joseph, Michigan, the oncologist wanted to start her on a highly potent combination of chemotherapy drugs that night, and Pompey agreed. But she also sought a second opinion on her treatment options at the University of Michigan.

“That’s where I learned about targeted therapy for my specific biomarker,” she recalled. “They never mentioned that at the other hospital.”

Pompey had ALK-positive lung cancer, so she received Xalkori (crizotinib), which targets ALK and ROS1 fusions. Her cancer didn’t progress for three-and-a-half years. But eventually, it spread to her brain. That’s when her oncologist switched her to a different ALK inhibitor called Alecensa (alectinib).

The drug shrank all her tumors. They are still visible but static. Today, her lungs, which were filled with fluid and caused her great difficulty breathing when she was diagnosed, have recovered their full capacity.

“My voice is hoarse this morning but that’s not because of the cancer,” she says. “I sang with the worship team at church yesterday. They like to have me rock out on this one rock-gospel song.”

Pompey’s story is not unusual. Though many life-prolonging targeted drugs are available to treat non-small cell lung cancer, comprehensive biomarker testing to match patients with those drugs is not a foregone conclusion at every health care facility. Some organizations, such as the American Society for Clinical Oncology, recommend that everyone with this type of cancer get tested for at least the most common drug targets. Some patient advocacy groups, such as the American Lung Association and LUNGevity, urge anyone with non-small cell lung cancer to ask their health care provider about comprehensive biomarker testing.

Paradigm Shift

Non-small cell lung cancer is just one cancer type for which medical societies are pushing for doctors to let genetic mutations be their guide. But basket trials could prompt this type of paradigm shift across many cancer types and lead to more “tumor-agnostic” drug approvals from the FDA. That means the drug would be approved to treat any type of cancer, regardless of where it originated, as long as it has a particular genetic mutation.

“We have a few drugs that have tumor-agnostic approval, but so many other targeted drugs do not,” says Dr. Monica Mita, a hematologist-oncologist and co-director of experimental therapeutics at Cedars-Sinai Medical Center in Los Angeles. “That’s one of the most interesting opportunities of tumor-agnostic studies.”

Basket trials also give researchers the opportunity to learn the role that certain tumor-driving gene mutations play in the overall behavior of the cancer. “It’s an opportunity to go beyond just seeing the cancer as a breast cancer or a colon cancer and to see it instead, for example, as a PI3K-mutated cancer,” Mita says.

The greatest beneficiaries of this study design may be people with rare cancers.

Cancers Too Rare to Study

Ann Rerat of Trumbull, Connecticut, learned she had leiomyosarcoma (LMS) of the uterus in 2017 when she was 60 years old. This rare but very malignant cancer can develop in any smooth muscle tissue, such as the digestive system, urinary system, blood vessels and uterus. Uterine LMS affects fewer than 1 in 100,000 women.

In cancers as rare as these, clinical trials are pretty uncommon. Researchers simply cannot enroll enough patients with the disease to study it properly. That’s why basket trials can be such a boon for people with these rare conditions. When researchers build study cohorts based on the genetic makeup of the tumor, rather than the tumor type, they may be able to enroll enough people with many different tumor types for a viable clinical trial.

After a hysterectomy, a targeted drug, an additional surgery and chemotherapy with docetaxel and gemcitabine, Rerat’s cancer continued to advance. She was at stage 4 and had a life expectancy of less than five years when Dr. David Hyman, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, invited her to participate in a basket trial. The JAVELIN BRCA/ATM trial tested the drug combo of the PD-L1 inhibitor Bavencio (avelumab) and PARP inhibitor Talzenna (talazoparib)
in people with advanced solid tumors that had either a BRCA1 or 2 gene mutation or an ATM mutation. Rerat was a match.

Talzenna is a daily pill and Bavencio is administered by IV infusion every two weeks. When Rerat started the drug combination in August 2018, she had tumors throughout her pelvic area. She went for scans every three months to monitor the drug’s efficacy.

On the first scan, the tumors were smaller. By the sixth, Rerat had no evidence of disease. Her scans have been clean ever since.

“I still don’t have the words to express what it was like to get those results,” she says. “Incredible. Grateful. It has changed my whole world.”

Basket trials may make this world-changing impact on many people with rare cancers.

“People with very rare tumors are an underserved population,” Mita says.

The DART trial aims to serve these patients. This trial tests the immune checkpoint inhibitor combination of Opdivo (nivolumab) and Yervoy (ipilimumab) in patients with any of a long list of rare solid tumors. A recent publication of the nonpancreatic high-grade neuroendocrine carcinoma group showed that 44% of patients with this type of tumor responded to the drug combo. In the angiosarcoma patient group, 25% responded.

As of June 20, 2021, about 60% of the 1,172 patients enrolled in the NCI-MATCH had rare or less common cancers. The trial defines “less common” as any cancers other than breast, colorectal, non-small cell lung or prostate. Among the less common cancers included in the trial are cancers of the central nervous system, kidney, liver and biliary tract, and neuroendocrine cells, among others.

“But you can also think of rare cancers as being defined by molecular aberration,” O’Dwyer says. “Some of these mutations occur in fewer than 1% or 2% of cancers, so in many regards each of these tumors is a rare tumor.”

That’s the case with the NRG1 fusions — the kind that Huggins has.

“NRG1 fusions are extremely rare; however, they are rare across many different disease types, so when you group them all together in a basket trial, you can study the effects of targeting this genetic alteration,” says Dr. Alison Schram, a medical oncologist at Memorial Sloan Kettering Cancer Center and principal investigator on the Zeno trial in which Huggins is enrolled. Schram and her colleagues recently reported that 42% of patients with NRG1 fusion-positive pancreatic cancer responded to the drug.

Tumor Type or Gene Mutation: Which Matters More?

For some, but certainly not all tumor types, basket trials have shown that mutations could be more important than tumor type in treatment decisions. Basket trials that studied the effects of Vitrakvi (larotrectinib) and Rozlytrek (entrectinib) in tumors with a genetic alteration called an NTRK fusion led to tumor-agnostic FDA approvals for these drugs.

Research has also found that tumors with RET fusions tend to respond to RET inhibitors regardless of the tumor type. The RET inhibitor Retevmo (selpercatinib) is approved to treat lung and thyroid cancers with this mutation. But investigators on the LIBRETTO-001 trial recently reported that 47% of patients with RET fusions across numerous cancer types responded to Retevmo.

“Basket trials enrolling patients on the basis of NTRK and RET fusions have yielded incredible results. These drugs benefit the majority of patients with the relevant biomarkers,” says Schram, who has been an investigator on trials of those drugs.

The massive NCI-MATCH trial’s 39 treatment groups, enrolling at nearly 1,100 cancer centers in all 50 states, Washington, D.C., and Puerto Rico, explore the efficacy of a number of drugs to treat tumors with various genetic abnormalities. The researchers have published the findings of 19 of those groups.

Among the findings, 38% of patients with BRAFv600E mutations responded to the drug combination of the BRAF inhibitor Tafinlar (dabrafenib) and MEK inhibitor Mekinist (trametinib). In patients without colorectal cancer whose tumors had what’s called a mismatch repair deficiency, 36% responded to Opdivo, an immunotherapy drug that targets PD-1. That data helped earn the drug tumor-agnostic approval from the FDA. Just over 28% of those with AKT1 E17K mutations responded to the AKT kinase inhibitor capivasertib.

But not all gene mutations trump cancer type. Research indicates, for example, that colorectal cancers tend to be harder to attack with gene-targeted therapies, as they are sometimes better suited for other cancers such as melanoma but not for gastrointestinal cancer.

“In these cancers, if you inhibit one pathway, another pathway can sometimes compensate, leading to continued cancer growth despite inhibiting the specific gene alteration,” Schram says.

For that reason, researchers are testing drug combinations to target multiple pathways simultaneously and will continue to design both the trials that group cancers by site or tumor type and basket trials that group cancers by their genetic makeup.

Because not all tumors have a strong response to targeted drugs, the jury is still out on whether everyone with metastatic cancer of any type should get genetic analysis of their tumor. “There’s a lot of controversy,” Schram says, “about the cost-benefit ratio of doing genomic sequencing on every tumor.” Some say the tests are too expensive to justify in people who have cancers for which there are no proven-effective targeted drugs. But on the other hand, with the advent of basket trials as well as the continually dropping price of DNA sequencing, genetic analysis could open the door to experimental treatments for people who may believe they are out of options.

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