- New research presented at this weekend's annual meeting of the American Society of Clinical Oncology (ASCO) points toward the hastening development of precision medicine in cancer research, a concept which promises to upend the traditional understanding of cancer by its site of origin in the body.
- Data from three clinical trials testing larotrectinib, a drug developed by Loxo Oncology, showed a 76% objective response rate in 50 adult and pediatric patients diagnosed with 17 different types of advanced cancer. Patients were identified by a genetic abnormality known as TRK fusion which, while rare, occurs across a wide array of cancers.
- While the data is early, Loxo saw enough to map out a path to the FDA. The Connecticut-based biotech expects to submit a New Drug Application for larotrectinib to the regulator sometime in late 2017 or early 2018, pending a positive primary analysis slated for later this year.
Last month, the Food and Drug Administration approved Merck’s blockbuster checkpoint inhibitor Keytruda (pembrolizumab) for treatment of tumors with a specific genetic signature — marking the first time the agency has cleared a drug based on a biomarker rather than on a tumor’s location in the body.
The approval was a step toward the promise of precision medicine in oncology, and a break from decades of clinical practice diagnosing patients by tumor site or organ. Loxo's research, though, suggests that Keytruda could soon have company.
Loxo’s interim data, which was collected from three early- to mid-stage trials, showed treatment with larotrectinib led to a partial or complete response in 76% of the 50 patients who were studied long enough to have confirmatory scans. Breaking that number down, six patients saw a complete response while 32 experienced a partial response.
Median duration of treatment and progression-free survival had not been reached as of data cut-off as 79% of responding patients remained progression free after 12 months of treatment.
Current data relied on response assessments from investigators at each clinical site. The primary analysis will require a separate review by independent radiologists.
Larotrectinib selectively targets tropomyosin receptor kinase (TRK) fusion proteins, which occur when one of three TRK genes fuses to another gene. These TRK fusions emerge as tumors grow and accelerate cell division. While rare in common cancers, these fusions can be more prevalent in some rare forms of cancer such as infantile fibrosarcoma.
"These findings embody the original promise of precision oncology: treating a patient based on the type of mutation, regardless of where the cancer originated," said David Hyman, the lead study author and head of early drug development at Memorial Sloan Kettering Cancer Center.
Patients included in the analysis at ASCO had a diverse range of cancer diagnoses, from advanced colon cancer and melanoma to cholangiocarcinoma and salivary gland carcinomas.
In three patients with infantile fibrosarcoma, treatment with larotrectinib in patients shrunk tumors enough to permit surgery.
Side effects were manageable, with fatigue and dizziness the most common. Seven patients required a dose reduction of larotrectinib due to an adverse event, although all seven experienced tumor regression continuing after the dose lowering.
More notably, however, six responded to larotrectinib but then subsequently progressed. Biopsies from five of the six showed a "consistent mechanism of acquired resistance," which lowered the binding potency of the drug. Loxo has another earlier-stage candidate, LOXO-195, that also inhibits TRK and is aimed at addressing acquired resistance.
While larotrectinib or Keytruda’s recent approval based on biomarkers more fully embody the aim of precision medicine, biomarkers are also increasingly being incorporated in traditional cancer drug development too.
According to a recent report from QuintilesIMS, 10% of currently ongoing late-phase cancer trial rely on biomarker-based patient segmentation. More generally, predictive biomarkers can help better stratify patients to zero in on those who are most likely to respond.
Immuno-oncology’s continued maturation could push this trend further along, as researchers seek to boost response rates and better understand why so many patients still don’t respond.