Larotrectinib Delivers 81% Overall Response Rate in an Expanded Dataset of 109 TRK Fusion Cancer Patients Across Ages and Tumor Types

-- Median duration of response (mDOR) in primary dataset not reached after follow-up of 17.6 months(1)

-- 18 percent of patients in the primary dataset experienced complete responses (CR), with the number of CRs increasing as the data matured(1)

-- Adult and pediatric patients in the integrated dataset had TRK fusion cancer across 24 unique tumor types, including common tumors like lung, thyroid, and colon, and rare tumors like salivary gland and infantile fibrosarcoma(1)

-- Larotrectinib is currently under Priority Review with the U.S. Food and Drug Administration (FDA) with Breakthrough Therapy, Rare Pediatric Disease, and Orphan Drug Designations

News provided by

Bayer

Oct 21, 2018, 05:12 ET

WHIPPANY, N.J., Oct. 21, 2018 /PRNewswire/ -- Bayer and Loxo Oncology, Inc. (Nasdaq: LOXO), today announced updated clinical data for larotrectinib in adult and pediatric patients with TRK fusion cancer across 24 unique tumor types. The update included approximately one year of additional follow-up for a primary dataset of 55 patients as well as results from a supplementary dataset of 67 patients.¹The overall response rates (ORR) in these groups were 80 percent and 81 percent, respectively, while the median duration of response (mDOR) had not yet been reached in either group.¹ Complete responses (CR) in the primary dataset continued to mature, increasing to 18 percent, while the additional patients in the supplementary dataset experienced a CR rate of 17 percent.¹ These data are being presented today at the ESMO 2018 Congress (European Society for Medical Oncology).

This is the only analysis to examine the efficacy and safety of a single-purpose drug for the treatment of TRK fusion cancer. The 122-patient integrated dataset (109 patients included in the efficacy analysis) included both adult and pediatric patients with TRK fusion cancer across 24 unique tumor types, ranging in age from approximately one month to 80 years.¹ Tumor types included 10 distinct soft tissue sarcomas, salivary gland, infantile fibrosarcoma, thyroid, lung, melanoma, colon, gastrointestinal stromal tumor, breast, bone sarcoma, cholangiocarcinoma, carcinoma of unknown primary, congenital mesoblastic nephroma, appendiceal, and pancreas cancers.¹ Safety results were generally consistent with previous presentations, with the majority of adverse events (AE) grade 1 or 2.¹ No treatment-related grade 3 or 4 AEs occurred in more than 5 percent of patients.¹

"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 single-purpose drugs against oncogenic driver targets, and underscores the importance of tumor genomic profiling capable of identifying NTRK gene fusions alongside other activating alterations."

"These data from a large patient group with TRK fusion cancer are truly encouraging – bringing us one step further to delivering this treatment to patients," said Dr. Scott Z. Fields, Senior Vice President and Head of Oncology Development at Bayer's Pharmaceutical Division. "We look forward to bringing this potential treatment option to adults and children with TRK fusion cancer as soon as possible."

The U.S. Food and Drug Administration (FDA) granted Priority Review for larotrectinib for the treatment of adult and pediatric patients with locally advanced or metastatic solid tumors harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. The FDA has set a target action date of November 26, 2018, under the Prescription Drug User Fee Act (PDUFA). Bayer has submitted a Marketing Authorization Application (MAA) in the European Union (EU) and additional filings in other markets are underway.

Detailed Results Presented at ESMO 2018 Congress
The ESMO 2018 Congress presentation included additional follow-up for the first 55 consecutively enrolled adult and pediatric patients with TRK fusion cancer treated across the Phase I adult trial, Phase II trial (NAVIGATE), and Phase I/II pediatric trial (SCOUT).¹ These patients were the subject of the New England Journal of Medicine publication and constitute the primary analysis population supporting larotrectinib's NDA filing. The presentation also included data for the 67 TRK fusion cancer patients subsequently enrolled.¹ Presented data were based on a July 30, 2018 data cut-off date, providing approximately one year of additional follow-up for the primary analysis population.¹

The datasets included patients with RECIST-evaluable disease enrolled to the three clinical trials, regardless of prior therapy or testing methodology used to establish their TRK fusion status.¹ In the ESMO 2018 Congress presentation, response evaluations were based on investigator assessment.¹

In the primary dataset, the overall response rate (ORR) was 80 percent (44/55) (95% CI: 67-90%), with a 62 percent partial response (PR) rate and an 18 percent complete response (CR) rate.¹ In the supplementary dataset, the ORR was 81 percent (44/54) (95% CI: 69-91%), with a 65 percent PR rate and a 17 percent CR rate.¹ Across both datasets, the ORR was 81 percent (88/109) (95% CI: 72-88%), with a 63 percent PR rate and a 17 percent CR rate.¹ The ORR analyses for the supplementary and integrated datasets included nine patients with unconfirmed PRs awaiting confirmatory response assessments; they did not include 13 patients who were awaiting an initial response assessment and continuing on study.¹

Median duration of response (mDOR) had not been reached in either the primary dataset or supplementary dataset, with median follow-up of 17.6 months and 7.4 months, respectively.¹ In the primary dataset, Kaplan-Meier landmark analyses improved since the July 2017 data cut-off date.¹ At six months, 88 percent of responses were ongoing (83 percent based on the July 2017 data cut-off date). At 12 months, 75 percent of responses were ongoing (71 percent based on the July 2017 data cut-off date). Kaplan-Meier landmark analyses of the supplementary dataset were highly concordant with the primary dataset.¹ At six months, 93 percent of responses were ongoing and at 12 months, 81 percent of responses were ongoing.¹ Across the integrated dataset, as of the July 2018 data cut-off date, 84 percent of responding patients remained on treatment or had undergone surgery with curative intent.¹

The safety data presented at the ESMO 2018 Congress encompassed the entire larotrectinib safety database in cancer patients (n=207). The majority of adverse events (AE) reported were grade 1 or 2.¹ No treatment-related grade 3 or 4 AEs occurred in more than 5 percent of patients.¹Of the 122 patients with TRK fusion cancer, 11 patients (9 percent) required larotrectinib dose reductions.¹ In all cases, patients whose doses were reduced maintained their best response at the lower dose.¹ One patient (<1 percent) discontinued larotrectinib due to an AE.¹

About Larotrectinib
Larotrectinib is an investigational tropomyosin receptor kinase (TRK) inhibitor in clinical development for the treatment of patients with solid tumors that harbor a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. Growing research suggests that the NTRK genes can become abnormally fused to other genes, producing a TRK fusion protein that can lead to the development of solid tumors across various sites of the body.^2-4

In November 2017, Bayer and Loxo Oncology entered into an exclusive global collaboration for the development and commercialization of larotrectinib and LOXO-195, a TRK inhibitor in clinical development. Bayer and Loxo Oncology will jointly develop the two products with Loxo Oncology leading the ongoing clinical studies as well as the filing in the U.S., and Bayer leading ex-U.S. regulatory activities and worldwide commercial activities. In the U.S., Bayer and Loxo Oncology will co-promote the products.

For additional information about the larotrectinib clinical trials, please refer to www.clinicaltrials.gov or visit www.loxooncologytrials.com. Larotrectinib has not been approved by the U.S. Food and Drug Administration, the European Medicines Agency or any other health authority.

About TRK Fusion Cancer
TRK fusion cancer occurs when a neurotrophic tyrosine receptor kinase (NTRK) gene fuses with another unrelated gene, producing an altered tropomyosin receptor kinase (TRK) protein.^2,3,5 The altered protein, or TRK fusion protein, becomes constitutively active or overexpressed, and triggers a signaling cascade.² These proteins become the primary oncogenic driver of the spread and growth of tumors.⁴ NTRK gene fusions have been identified in various adult and pediatric solid tumors with varying frequencies.⁴

About Oncology at Bayer
Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer now includes four oncology products and several other compounds in various stages of clinical development. Together, these products reflect the company's approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated.

About Bayer
Bayer is a global enterprise with core competencies in the Life Science fields of health care and agriculture. Its products and services are designed to benefit people and improve their quality of life. At the same time, the Group aims to create value through innovation, growth and high earning power. Bayer is committed to the principles of sustainable development and to its social and ethical responsibilities as a corporate citizen. In fiscal 2017, the Group employed around 99,800 people and had sales of EUR 35.0 billion. Capital expenditures amounted to EUR 2.4 billion, R&D expenses to EUR 4.5 billion. For more information, go to www.bayer.us.

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Forward-Looking Statement
This news release may contain forward-looking statements based on current assumptions and forecasts made by Bayer Group or subgroup management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer's public reports which are available on the Bayer website at www.bayer.com. The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

References
1.	Lassen, Ulrik, Albert, Catherine, Kummar, Shivaani, et al. Larotrectinib efficacy and safety in TRK fusion cancer: an expanded clinical dataset showing consistency in an age and tumor agnostic approach. In: Proceedings from the European Society for Medical Oncology 2018 Congress; October 21, 2018; Munich, Germany. Abstract 409O.
2.	Amatu A, Sartore-Bianchi A, Siena S. ESMO Open. 2016;1(2):e000023.
3.	Vaishnavi A, Le AT, Doebele RC. Cancer Discov. 2015;5(1):25-34.
4.	Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. The landscape of kinase fusions in cancer. Nat Commun. 2014;5:4846. doi:10.1038/ncomms5846.
5.	Kumar-Sinha C, Kalyana-Sundaram S, Chinnaiyan AM. Landscape of gene fusions in epithelial cancers: seq and ye shall find. Genome Med. 2015;7:129. doi:10.1186/s13073-015-0252-1.