NEW YORK (GenomeWeb) – In developing the cancer drug LOXO-101 for patients with rare TRK fusions, Loxo Oncology is enrolling study participants from around the country who have received genomic testing from CLIA-certified labs.
The company is also recruiting patients with TRK fusions and different types of cancer into a Phase II basket trial. Data from this study may eventually support Loxo's discussions with the US Food and Drug Administration to garner a "molecular label" for its drug.
Precision medicine enthusiasts have long predicted that advances in genomics will turn the traditional drug development paradigm on its head. Some have predicted that in the future drugs will be approved with "molecular indications" — genomic markers that are drivers of a range of different cancers — instead of drugs for breast cancer or lung cancer.
Loxo, a drug company focused on cancers driven by genomic abnormalities, is developing its lead product, LOXO-101, with just such a future in mind. At the American Association for Cancer annual meeting in New Orleans, the company presented updated data from a Phase I study which showed that a small number of patients with TRK fusions saw their tumors shrink and are continuing to respond to its investigational TRK inhibitor.
These patients, who have a variety of different cancers, received testing through Foundation Medicine, which identified that their cancers had TRK fusions. Their doctors referred these patients to the Loxo Phase I study.
"These were patients that were found in the community largely based on routine testing," Jacob Van Naarden, Loxo's chief business officer, told GenomeWeb. "They heard about our drug, they heard that our drug was specifically designed, and they found their way to our study."
As of the March 25 cut-off date, seven out of 43 patients in the Phase I study had TRK fusions. At AACR, David Hong from the MD Anderson Cancer Center presented data showing that five patients with TRK fusions have achieved a partial response according to RECIST (Response Evaluation Criteria In Solid Tumors) criteria, meaning that lesions have shrunk by 30 percent or more.
The first patient in the Phase I study, a woman with soft tissue sarcoma that had spread to the lungs, was evaluated on Foundation Medicine's FoundationOne Heme profiling test, which identified a LMNA-NTRK1 fusion.
The second patient with an ETV6-NTRK3 fusion has a gastrointestinal stromal tumor; the third and fourth patients with ETV6-NTRK3 fusions have mammary analogue secretory cancer of the salivary glands; and the fifth patient with an ETV6-NTRK3 fusion has papillary thyroid cancer.
The sixth patient, a 28-year-old male with non-small cell lung cancer had cancer in other areas of his body, including bone, lymph nodes, and the brain. In the Phase I study, he experienced tumor shrinkage at all sites, including in the brain, and has stable disease, but he hasn't met RECIST criteria yet. This patient doesn't have any pain and cough and he is now training for the Boston marathon, Loxo CEO Joshua Bilenker told investors on a conference call to discuss the AACR data.
The seventh patient was enrolled recently and did not have response data as of March 25. None of the six evaluable patients, all of whom were heavily pretreated with other drugs, showed signs of cancer progression as of the cut-off date.
Experience with next-generation ALK and EGFR inhibitors suggests that "when you hit a target very deeply and well, you tend to get better durability," said Bilenker, who is a partner at Aisling Capital, a founding investor in Loxo. This is what LOXO-101 seems to be doing, he told investors, as a likely explanation for why patients with TRK fusions haven't yet progressed.
The patients in the Phase I study who don't have TRK fusions haven't benefitted from LOXO-101, but these patients are providing information about the safety of drug. Loxo reported all observed adverse events in the study, even if they weren't due to the drug. The data so far shows patients in the trial experienced Grade 1 and 2 adverse events, such as fatigue, constipation, and dizziness, some Grade 3 toxicities, but no Grade 4 events. One patient with a TRK fusion, who experienced some dizziness early in treatment, had his drug dose reduced from 100 mg twice a day to once a day, but his tumor continued to shrink.
We don't want to disrupt what you normally do. Let's work our trial into how you routinely manage patients.
Drug development in the genomic era
One of the key insights from the Phase I study is the diversity of tumor types in which TRK fusions have been identified. TRK fusions are rare in cancer and tissue is often scarce in advanced patients. Doctors and researchers alike want to get as much information as possible on the molecular characteristics of a patient's cancer in one go.
Therefore, it makes sense to use comprehensive genomic profiling to identify patients for the LOXO-101 development program. Other than Foundation Medicine, a number of US cancer centers, as well as commercial and academic labs, provide comprehensive genomic profiling services. Advocacy groups have launched programs to educate and expand access to such testing services for patients in the community setting, where 80 percent receive care.
"One of the stories of our company and this particular therapeutic program is the democratization and increased clinical utilization of next-generation sequencing with good sensitivity to actually find these genetic events," Van Naarden said.
As such, the firm hasn't inked a traditional companion diagnostic deal with any one test developer for LOXO-101, and it is enrolling patients with TRK fusions from around the country who received testing through different labs.
Doctors ordering genomic profiling tests for their patients have relationships with labs that they prefer to use and want to keep using. In order to identify genomic alterations that occur in as few as 1 percent of cancer patients, they might not want to use the specific lab that a drugmaker has partnered with. By the time they want to refer patients to a clinical trial, doctors may already know if they have a TRK fusion, Van Naarden reflected. So, doctors have wondered why they couldn't just enroll the patient in the study?
"We heard that feedback and said, 'Great, we don't want to disrupt what you normally do. Let's work our trial into how you routinely manage patients,'" he said.
Growing importance of genomic profiling in cancer care has created challenges for health regulators evaluating the safety and efficacy of drugs and tests. FDA officials have spoken publicly about the difficulties they face when doctors "prescreen" patients for genetic markers and then refer them to drug trials investigating that specific subset of patients.
The result is that more patients with the marker of interest come into the study, but not those without the marker. "This could be very good for patients," an FDA official said several years ago. "On the other hand, it could cause some headaches for the evaluation of the diagnostic test, and maybe even cause some bias in the estimation of the performance of the therapy."
Prescreening was a concern in the development program for Pfizer's non-small cell lung cancer drug Xalkori (crizotinib), which the agency approved in 2011 with a companion test that could identify patients with ALK rearrangements. "[Xalkori] was the first example in the modern era of a rare genomic alteration defining a population sensitive to a drug," Van Naarden said. "As the first one, FDA and Pfizer, I think, collectively struggled with how to handle that whole process including diagnostics."
As increasingly rarer and rarer genomic markers are identified in cancer, the FDA has had to become more flexible. Notably, last month, the agency approved a new indication for Xalkori in NSCLC patients with ROS1 alterations without a companion diagnostic to identify this rare subpopulation.
Of the 1.5 million new cases of NSCLC worldwide each year, approximately 15,000 cases are characterized by the ROS1 fusion. It took Pfizer several years to gather data on 50 NSCLC patients with ROS1-positive tumors and submit the data on Xalkori to the FDA.
Recognizing the unmet need in this population, the FDA approved Xalkori's new indication with a post-marketing commitment for Pfizer to develop a CDx in the future, leaving open the opportunity to advance a next-generation sequencing panel test. Pfizer inked a deal with Thermo Fisher Scientific last year to develop an NGS-based companion test that will be used as part of multiple NSCLC drug development programs.
"They've never done that before," Van Naarden said, referring to the FDA's latest Xalkori approval in the ROS1 subpopulation. "And that study was enrolled entirely based on CLIA-certified lab-developed tests."
We'll collect the data and see what regulators want to do.
Next steps
In addition to the Phase I trial , Loxo is studying LOXO-101 in a Phase II basket trial in adult patients with solid tumors with TRK fusions, and in a Phase I pediatric trial in all comers. Later this year, the NCI-MATCH study will open an arm that will enroll patients with TRK fusions who will receive TRK inhibitors.
In the Phase II trial, researchers will enroll patients into separate baskets for NSCLC, sarcoma, thyroid, colorectal, salivary, and billiary cancers. The seventh and eighth baskets will enroll patients with central nervous system tumors and all other solid tumors. According the clinicaltrials.gov webpage for the study, it will include patients with "locally advanced or metastatic malignancy with an NTRK1, NTRK2, or NTRK3 gene fusion, identified through molecular assays as routinely performed at CLIA or other similarly certified laboratories."
"Depending on the degree of efficacy we see, we believe this trial has the potential to enable registration of LOXO-101," Bilenker told investors during the call. Van Naarden told GenomeWeb that the firm has discussed the study protocol with the FDA, and the agency is aware that patients will be tested on LDTs.
Loxo is also banking tumor tissue in this study and performing concordance testing with centrally performed assays. "We won't use that as a gating item for enrollment but … we'll look at that and even reanalyze our efficacy data through the lens of the central test, just in case there are false negatives or false positives," Van Naarden said.
The Phase II basket study also raises questions about how FDA and Loxo will negotiate the indication for LOXO-101. Will it carry a traditional indication for, say NSCLC, or will it carry a broad "molecular indication" covering multiple tumor types defined by TRK fusions in which the drug is efficacious?
"We'll collect the data and see what regulators want to do," Van Naarden said, adding that if regulators aren't ready for a "molecular label," Loxo will submit data from prospectively enrolled cohorts on specific tumor types.
Although patients in the Phase I study continue to respond to LOXO-101, it is likely that patients will experience progression after some time as their cancer cells acquire resistance. The remarkable initial responses seen with precision cancer drugs inevitably always seem to give way to progression.
Loxo is already working on a next-generation TRK inhibitor with LOXO-195. The drug is "structurally unique" from LOXO-101 and binds differently to the kinase domain.
Once TRK fusion-positive patients progress on LOXO-101 or other inhibitors, "we hope to have LOXO-195 ready as a relevant next step for the patient," Bilenker said. The company is planning to study LOXO-195 in Phase I trials next year.