- On Saturday, Loxo Oncology reported positive interim data from a Phase 1, dose-escalating trial that's testing its cancer medicine LOXO-292 in patients with certain types of genetic abnormalities.
- Investigators had enrolled 82 patients in the trial by April 2. Though the participants came with various cancers, including non-small cell lung, thyroid and pancreatic, one area of commonality for almost all of them was genomic fusions in an enzyme called rearranged during transfection (RET) kinase. When such changes happen, patients can develop uncontrolled cell growth and ultimately cancer.
- The overall response rate was 77% for the patients with RET fusion-positive cancers and 45% for those with RET-mutated medullary thyroid cancer (MTC), of which there were 29 recruited for the trial and 22 eligible for response evaluation by the data cut-off. Four patients with no known activating RET alterations were also evaluated, but that group showed no ORR.
Much of the attention directed at Loxo so far has been because of its lead candidate, larotrectinib, a tropomyosin receptor kinase (TRK) inhibitor. Yet the new data presented over the weekend at the American Society of Clinical Oncology's annual meeting builds the case that Loxo's potential isn't rooted in a single asset.
Loxo's drug development platform revolves around medications that go after tumor genetic expression rather than a specific tissue. It's a strategy gaining traction across the industry, as it offers a highly targeted mode of treatment; just over a year ago, Merck & Co. notched a first-of-its-kind approval when the Food and Drug Administration OK'd Keytruda (pembrolizumab) for certain patients with colorectal cancer or solid tumors that have an uncommon mutation, dubbed deficient mismatch repair, or high levels of microsatellite instability.
To underscore the trend further, Bayer dropped $400 million upfront in November to gain ex-U.S. rights to larotrectinib and another, earlier-stage Loxo TRK drug. The biotech's stock has felt the love as well, with shares up nearly 300% over the last year.
In addition to the early ORR data, Loxo disclosed that the bulk of treatment-emergent adverse events were Grade 1, and that the most common were fatigue, diarrhea, constipation and dry mouth, though these were seen "regardless of relationship to LOXO-292," according to the company.
Two patients experienced treatment-related adverse events at Grade 3 or higher: one case of tumor lysis syndrome, and one of increased liver enzymes. The patient with the tumor lysis syndrome was on the 240 mg twice daily regimen, and was the only observed case of dose-limiting toxicity.
The results put Loxo in an advantageous position to rival RET-drugmaker Blueprint Medicine, which in early April announced proof-of-concept data from an ongoing Phase 1 study of its candidate, BLU-667. The drug elicited a somewhat similar safety profile to LOXO-292 — albeit with a considerably higher portion of patients experiencing elevated enzyme levels — but preliminary ORR was 50% in NSCLC patients and 40% in MTC patients who were eligible for response evaluation.
LIBRETTO-001, the Phase 1 study of LOXO-292, has eight dose escalation cohorts. They ranged from as low as 20 mg once a day to 240 mg twice a day.
Of the patients enrolled in the trial, many were pre-treated with multikinase inhibitors (MKIs). Just about half had received prior chemotherapy, and about a quarter had received prior immunotherapy. The breakdown went as follows:
|Type of cancer||Total # of patients||RET status||# Pre-treated with MKI|
|Non-small cell lung cancer||38||fusion-positive||21|
|Medullary thyroid cancer||29||mutated||23|
|No known activating RET alterations||4||N/A|
Researches noted too that LOXO-292's anti-tumor activity wasn't dependent on any specific RET fusion partner (of which there can be a few), RET mutation or prior MKI treatment. The data also showed evidence of durability, as 90% and 93% of RET fusion-positive and RET-mutant MTC patients, respectively, stayed on therapy. By April the longest-treated patient had been receiving Loxo's drug for 10 months.
Loxo intends to present additional data on LOXO-292's ability to reduce and clear RET in a separate ASCO presentation on June 3.