Bayer, Loxo to Collaborate on Larotrectinib

Przemyslaw W. Twardowski, MD

Bayer and Loxo Oncology have entered into a partnership to develop and market larotrectinib (LOXO-101) and LOXO-195 in the United States and worldwide. Both agents are investigational tropomyosin receptor kinase (TRK) inhibitors.

Larotrectinib is an oral, selective TRK inhibitor and LOXO-195 is an investigational next-generation, selective TRK inhibitor capable of addressing potential mechanisms of acquired resistance that may emerge in patients receiving larotrectinib or multikinase inhibitors with anti-TRK activity. In findings presented at the 2017 ASCO Annual Meeting, larotrectinib was associated with a 75% response rate in patients with a range of TRK fusion—positive solid tumors.

“We see great potential in larotrectinib and the follow-on compound LOXO-195, which has the potential to provide additional benefit for patients who might progress on an initial TRK inhibition therapy,” Robert LaCaze, executive vice president and head of the Oncology Strategic Business Unit at Bayer, said in a press release. “These agents have the potential to fulfill the promise of precision medicine—where tumor genetics rather than tumor site of origin define the treatment approach for patients.”

Under the terms of the agreement, Loxo will receive an upfront payment of $400 million. The company can receive another $450 million in milestone payments upon larotrectinib regulatory approvals and first commercial sale events in certain major markets, and an additional $200 million in milestone payments if and when LOXO-195 hits those same targets.

Bayer will lead ex-US regulatory activities and worldwide commercial activities. Loxo Oncology will lead global development activities and US regulatory activities. Worldwide, the 2 companies will split development costs 50/50. Both companies will promote the products in the United States and will share commercial costs and profits equally.

TRK gene fusions are genetic alterations that appear across a wide range of tumors—including breast and colorectal cancer, infantile fibrosarcoma, lung cancer, melanoma, and various sarcomas—and lead to uncontrolled TRK signaling and tumor growth. Such fusions are rare, but they are expressed in dozens of adult and pediatric of tumor types. To date, researchers have identified more than 50 different partner genes that fuse with 1 of 3 TRK genes (NTRK 1, 2, and 3).

The results presented at ASCO by David Hyman, MD, chief of early drug development at Memorial Sloan Kettering Cancer Center, involved 55 TRK fusion—positive adult and pediatric patients with advanced solid tumors representing 17 unique cancer types.

Patients were recruited into 1 of 3 phase I/II clinical trials based on local testing, which investigators said represented “real world” experience, and were assigned to 100 mg of larotrectinib twice daily. Fifty patients for whom confirmatory response data were available were included in this analysis.

The overall response rate by investigator assessment (ORR) was 76% (95% CI, 62-87), including a partial response rate of 64% and a complete response rate of 12%. Five additional patients who joined the study too early to have had their confirmatory scans all had at least a partial response to larotrectinib.

In an analysis of all 55 RECIST-evaluable patients, larotrectinib was associated with an independently-reviewed ORR of 75% (95% CI, 61-85), with a confirmed ORR of 80% (95% CI, 67-90). The results were consistent across tumor types, and Hyman noted that 93% of responding patients and 75% of all patients have remained on therapy or undergone surgery with curative intent.

The FDA in May 2017 granted orphan drug designation to larotrectinib for the treatment of solid tumors harboring NTRK-fusion proteins. In July 2016, the agency awarded the drug breakthrough therapy designation for adults and pediatric patients with unresectable or metastatic solid tumors with NTRK-fusion proteins who require systemic therapy, and who have either progressed following prior treatment or who have no acceptable alternative treatments.

LOXO-195 is an oral and selective new drug in clinical development for the treatment of patients with cancers that have acquired resistance to initial TRK therapy, which may emerge due to TRK kinase point mutations. LOXO-195 was designed to treat these new point mutations and induce a new response.

Hyman DM, Laetsch TW, Kummar S, et al. The efficacy of larotrectinib (LOXO-101), a selective tropomyosin receptor kinase (TRK) inhibitor, in adult and pediatric TRK fusion cancers. J Clin Oncol. 2017;35 (suppl; abstr LBA2501).