ESMO18: As larotrectinib nears FDA decision day, Bayer and Loxo post latest positive data

Bayer
Bayer bought into Loxo's drug last November, and now both await a November FDA decision. (Bayer)

Bayer and Loxo Oncology have published the latest updated data, with long-term follow-up and an additional cohort, for their site-agnostic cancer drug larotrectinib at ESMO this weekend as they await a late November decision on a possible approval.

Loxo’s drug, which a just under year ago partnered up with Germany’s Bayer, is designed to work in a subset of cancer patients with TRK fusion.

Larotrectinib—a pan-tropomyosin receptor kinase (TRK) inhibitor—ties in with a trend among cancer drugs seeking approval based on a molecular target or biomarker, rather than the organ or tissue in the body where the tumor originates.

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Merck & Co. was the first to claim an FDA approval on that basis, getting a green light for its checkpoint inhibitor Keytruda (pembrolizumab) in microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors last year. Bayer and Loxo now want to join this class.

In the latest update, the 100-plus patient integrated dataset includes both adult and very young patients, who ranged in age from just one month to 80 years across 24 different tumor types, including cancers of the salivary gland, thyroid, lung, colon, infantile fibrosarcoma and sarcomas.

Previous data show that when given to 55 patients with 17 types of TRK fusion-positive cancer, the pan-TRK inhibitor achieved an objective response rate of 75%.

Now, the pair have posted results from an expanded dataset at the European cancer congress, which “showed continued robust antitumor activity.”

These latest data mixed those initial 55 patients from primary dataset, and added in a supplementary dataset of 67 patients, all with TRK fusion cancer across various tumor types.

The companies say that these combined showed an overall response rate (ORR) of 81%, with 63% partial responses (PR) and 17% complete responses (CR).

For those initial 55 patients, ongoing responses after a year were 75% with longer follow-up; ongoing responses in the supplementary dataset were 81% at 12 months.

Patients in the primary dataset continued to improve on larotrectinib with CRs increasing from 16% to 18% and corresponding PRs decreasing slightly from 64% to 62%. The pair add that the median duration of response has not been reached at a respective follow-up of 17.6 and 7.4 months.

“It is exciting to see larotrectinib deliver responses to patients in these studies with TRK fusion cancer, across different ages, tumor sites of origin, or CNS involvement,” said Ulrik Lassen, M.D., Ph.D., Department of Oncology, Rigshospitalet, Copenhagen.

“In the supplementary set, the response rate is nearly the same as in the primary set and duration of response has actually increased with longer patient follow-up. The larotrectinib experience provides strong clinical evidence supporting the development of singlepurpose drugs against oncogenic driver targets, and underscores the importance of tumor genomic profiling capable of identifying NTRK gene fusions alongside other activating alterations.”

He told FierceBiotech that there is a plan to analyze progression-free survival and overall survival, and that the results “will be presented at a future medical meeting, when data are more mature.”

He still sees ORR, which is the primary endpoint of the test, as “a direct measure of drug antitumor activity, which can be evaluated in a single-arm study.”

RELATED: Bayer pays $400M upfront to buy into Loxo cancer drugs

The Bayer/Loxo drug was awarded a priority review by the FDA in May for locally advanced or metastatic solid tumors harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, with a target action date of Nov. 26.

In November last year, Bayer paid $400 million (€340 million) and committed to more than $1 billion more to buy into Loxo’s tropomyosin receptor kinase (TRK) inhibitor franchise. The agreement puts Bayer in charge of global commercialization of the drug.

The eventual success of Bayer and Loxo’s candidates clearly depends on patients being screened for their respective biomarkers in the first place, and to that end Loxo formed an alliance with diagnostics and gene sequencing specialist Illumina last year to develop a tumor-profiling test that can be carried out on a patient biopsy or surgical specimen.

The aim is to develop a broad screen that takes in the majority of tumor biomarkers tied to a reimbursement pathway, which would avoid relying on a specific diagnostic for a rare mutation, which could be a drag on uptake.

On this, Bayer told us: “Bayer and Loxo Oncology are encouraged by the recent FDA approvals in the [next-generation sequencing] NGS space and the Medicare national coverage determination. We are working with many of the key players and see all of these as critical steps towards broader adoption of NGS.”

The company said the pact with Illumina will “seek approval for a version of the Illumina’s test, TruSight Tumor 170, as a potential CDx for larotrectinib. The test will allow local laboratories to provide referring physicians with comprehensive genomic information, so that patients can be matched to the most appropriate therapeutic options.”

Back in 2017, Loxo also asked Ventana Medical Systems to develop and commercialize a pan-TRK immunohistochemistry test, which is still in development.

And testing may help identify more patients, and potentially more commercial value, in the future, as Lassen explains: “TRK fusion cancer occurs across different solid tumors, in both adult and pediatric patients, with varying frequency, including appendiceal cancer, breast cancer, cholangiocarcinoma, colorectal cancer, gastrointestinal stromal tumor (GIST), infantile fibrosarcoma, lung cancer, mammary analogue secretory carcinoma of the salivary gland, melanoma, pancreatic cancer, thyroid cancer and various sarcomas.

“A precise number of patients with TRK fusion cancer is difficult to quantify; however, with more testing and diagnostic availability, it should be easier to hone in on that number.” But they wouldn’t be drawn on peak sales potential, given that more patients could be sought out and treated in the future.

Roche also presented new data at ESMO on its similar med, entrectinib, across several early-to-mid-phase tests.  

The drug shrank tumors in more than half (57.4%) of people with neurotrophic tropomyosin receptor kinase (NTRK) fusion-positive solid tumors.

ORR for entrectinib were seen across 10 different solid tumor types (median duration of response was 10.4 months). Roche is working hand-in-hand with its recent $2.4 billion buy Foundation for a diagnostic for this drug.

It’s a bit further behind Bayer/Loxo in the approval race, but does have an FDA Breakthrough tag, specifically in the treatment of NTRK fusion-positive, locally advanced or metastatic solid tumors in adult and pediatric patients who have either progressed following prior therapies or have no acceptable standard therapies.

It said it will now also add these data to the mix: “Genentech plans to submit results from these integrated analyses to global health authorities for the treatment of NTRK fusion-positive solid tumors and ROS1-positive non-small cell lung cancer,” the Swiss major said in a release over the weekend.