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Drugmakers Increasingly Using Basket Trials to Gain Precision Medicine Insights, ASCO Studies Show


CHICAGO – Drug companies are increasingly utilizing basket trials to efficiently gain insights into small, molecularly defined subpopulations of patients who might benefit from their investigational and marketed drugs.

As industry invests in such trials, however, it remains to be see whether the US Food and Drug Administration will accept data from these studies for registration trials and whether payors will reimburse for next-generation sequencing conducted as part of such investigations.

Using a basket trial, called MyPathway, for example, Genentech is hoping to quickly identify new molecularly defined subpopulations of patients who might benefit from treatments currently approved for other indications. Researchers presented preliminary results at the American Society of Clinical Oncology's annual meeting from the ongoing, open-label Phase II study involving more than 100 patients with advanced cancers.

The study includes Herceptin (trastuzumab) plus Perjeta (pertuzumab), which is currently approved for HER2-positive breast cancer; Zelboraf (vemurafenib), approved in BRAF-mutated melanoma; Erivedge (vismodegib), available for basal cell carcinoma; and Tarceva (erlotinib), marketed in EGFR-mutated non-small cell lung cancer.  

Although the number of precision medicines, such as Herceptin, Zelboraf, and Tarceva, have grown in recent years, John Hainsworth from the Sarah Cannon Research Institute noted at the conference that researchers have known that HER2, BRAF, and EGFR mutations show up in other cancer types at lower frequencies. "It's been difficult to test how effective these treatments are in other cancers due to the difficulty in identifying the patient population," said Hainsworth. "With an increase in comprehensive genomic profiling that's been going on in the last few years, we're identifying more and more of these unusual mutations in other cancers."

In MyPathway, investigators accepted patients who previously had next-generation sequencing, or FISH, or IHC testing for HER2-over expression or amplification in a CLIA-certified lab, according to Hainsworth.

Basket studies are a relatively new investigational strategy in which researchers genomically profile patients and quickly test out their hypotheses about whether certain molecular aberrations are targetable by specific drugs. To date, 129 patients have enrolled in Genentech's MyPathway basket study. In order to be eligible, patients had to have the genomic alterations of interest in tumor types for which a marketed drug doesn't exist and be refractory to other standard treatments.

Twenty nine of the patients in the study saw their tumors shrink by at least 30 percent, and researchers have not seen any new safety issues crop up. Approximately half the patients saw their disease progress after six months, while 15 patients are continuing to respond to treatment, some of them for more than 11 months.

Of the 129 patients, 61 had tumors with HER2 amplification. In this group, half of 20 colorectal cancer patients, more than 60 percent of eight bladder cancer patients, and all six biliary cancer patients experienced clinical benefit from the Herceptin/Perjeta regimen. To a lesser degree, some NSCLC, pancreatic, and head and neck cancer patients with HER2-positive tumors responded to treatment. Across all baskets, 28 percent of patients saw their tumors shrink.

In the study, 33 patients with BRAF mutations have been enrolled. Out of 15 NSCLC patients, 33 percent saw clinical benefit with Zelboraf, while three out of four ovarian cancer patients and one out of three patients with cancers of unknown primary origin also saw treatment benefit. Overall, 24 percent, or eight patients, across six cancer types experienced tumor shrinkage. Particularly of interest, noted Hainsworth, is that seven of these patients had BRAF V600E mutations, and Zelboraf is specifically approved for melanoma patients who have these types of mutations.

"I think we've shown now that this trial design is feasible where patients are selected on the basis of molecular abnormalities in their cancers rather than on their primary tumor type or primary site," he said, noting that patients had responses across 12 different tumor types outside of currently approved indications. "It certainly offers opportunities for patients with these molecular abnormalities."

Edith Perez, Genentech's VP and head of BioOncology, US Medical Affairs, told GenomeWeb that the firm will expand the HER2-positive colorectal, bladder, and biliary, and the BRAF mutation-positive NSCLC cohorts based on the early signals seen in the MyPathway study. "Using the basket study approach, it is possible to combine what would have been multiple trials into a single study, allowing us to learn more about the diseases and the potential of different treatment regimens," Perez said. "Basket studies allow us to more quickly identify which medicines may have promise based on signals that suggest clinically meaningful benefit."

The MyPathway trial, funded by Genentech, will enroll up to 500 patients, and as of last week had accrued 200 participants. Subgroups that appear to benefit from treatment will be expanded, but researchers will strop accruing in study arms when patients don't seem to respond. Researchers will also add new baskets, such as one where patients with BRAF mutations receive the MEK inhibitor Cotellic (cobimetinib) plus Zelboraf.

Sumanta Kumar Pal, an ASCO spokesperson, noted at the meeting that the MyPathway study is an efficient research protocol using a "tumor-agnostic approach," allowing investigators to study how, for example, bladder cancer patients may fare when they receive a drug typically used for breast cancer. Recognizing the efficiency of this approach, other drugmakers, such as Novartis, are exploring the basket trial design as a way to identify new treatment response signals.

A few years ago, Novartis launched the Signature Program, a drug trial series in which patients are enrolled into one of eight mutation-specific study protocols. Researchers at ASCO presented data showing that in the basket involving the drug ribociclib, four patients with CDK4/6 pathway alternations with various tumor types derived some benefit. Novartis is studying the drug in breast cancer and other solid tumors. 

Last year, ASCO launched TAPUR, in which it is enrolling advanced cancer patients with different types of solid tumors, multiple myeloma, or B-cell non-Hodgkin lymphoma, and prescribing them drugs based on genomic markers characterizing their disease. At the meeting, ASCO announced that two new drug firms, Bayer and Merck have joined six other drugmakers — Astellas, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Genentech, and Pfizer — who are providing 15 targeted treatment options at no cost to patients within the study. 

Since TAPUR opened in March this year, researchers have enrolled 16 participants who are receiving treatment, while 31 patients have given consent and have been or are being screened. Currently, 37 study sites around the country are enrolling patients, but as many as 100 sites have expressed a desire to join the study.

TAPUR is unique because it has a broad eligibility criteria, allows doctors flexibility by allowing them to choose the specific tissue or blood-based genomic profiling test they want to use, and is using Syapse's Precision Medicine Platform to manage the study's workflow from registering patients to facilitating the molecular tumor board's review of patient data. The molecular tumor board within TAPUR is using Illlumina's BaseSpace Cohort Analyzer and KnowledgeBase to inform their case review work. The study will also survey oncologists to gather insights on how they're using genomic testing, which could help inform physician education efforts.

As more evidence accrues from basket trials, treatment strategies in oncology may eventually shift from primarily site-specific to more molecularly focused approaches. However, experts at the meeting noted that tumor histology will likely continue to be an important consideration in precision medicine, since there is heterogeneity in the way a particular mutation behaves across tumor types.

But the shift toward molecularly guided treatment will happen slowly, predicted ASCO Chief Medical Officer Richard Schilsky. "I don't think we're close to being able to do that yet."

Offering the perspective of a national insurer, Lee Newcomer, senior VP at UnitedHealthcare in charge of oncology, genetics and women's health, said basket trials provided a rational way of exploring precision medicine approaches. He cited a study published last year in the New England Journal of Medicine involving patients with a range of cancers with BRAF V600 mutations, where researchers led by Memorial Sloan Kettering Cancer Center's Jose Baselga and David Hyman found that certain tumor types — like lung cancer or Langerhans cell histiocytosis — but not all tumor types appeared to respond to the BRAF inhibitor Zelboraf (vemurafenib).

Researchers wouldn't have discovered that patients with Langerhans cell histiocytosis — a rare disease where a type of white blood cell builds up in the body and forms tumors — respond well to Zelboraf if they hadn't systematically tested the drug across different types of cancer, Newcomer said. He added that as a result there are now some 28 patients receiving treatment for six months who haven't relapsed yet. "That's enough evidence that I think payors ... will soon begin recognizing that as reimburseable therapy," Newcomer said. "It's solid evidence."

If there was a nationally organized effort to make basket trials accessible for all cancer patients, not just those near a major cancer center, Newcomer believes payors could eventually warm to the idea of paying for NGS testing as a standard tool to investigate precision medicine approaches for patients. He proposed stakeholders work together to get 100,000 cancer patients into basket trials over the next three years.

"I think you'd see genetic sequencing would become a standard of care that would be reimbursed by payors," he said. "We're not there yet, but if that infrastructure developed, it's an easy next step for payors to start participating."

Meanwhile, it is also a matter of debate whether the FDA will consider data from basket trials sufficient for registering drugs, but Gary Schwartz, chief of hematology and oncology at NewYork-Presbyterian/Columbia University Medical Center, told GenomeWeb that the medical oncology community thinks the agency should accept such data. "The ultimate decision for FDA for registration may in part depend on the magnitude of the improvement noted with this approach, including improvement in progression-free survival and overall response rate," Schwartz said.

Currently, it's unclear what level of benefit seen in a basket study would convince the agency that they are useful for purposes beyond signal finding. But if basket trials are successful, these kinds of studies "could help shape the future of medical oncology," Schwartz said. "If effective, it will provide compelling proof that it is not the tumor type but the genetic code that is required for proper drug selection and ultimately FDA registration."