RET Inhibitor Prompts Roche–Blueprint Alliance

The battle of the RET inhibitors is heating up, with Blueprint Medicines, the company behind pralsetinib (BLU-667), partnering with Roche to jointly develop and commercialize the targeted agent for RET-driven malignancies. Industry analysts widely expect that pralsetinib will earn FDA approval by year's end to treat thyroid and lung cancers that harbor RET alterations. European approvals could follow in 2021.

The deal—which includes up-front payments totaling $775 million and the potential for as much as $927 million more—sets up Roche to compete directly with Eli Lilly. Last year, Lillyacquired Loxo Oncology in an $8 billion takeover; Loxo developed selpercatinib (Retevmo), the first RET inhibitor to reach the market.

Selpercatinib was approved in May to treat advanced cases of RET fusion–positive non–small cell lung cancer (NSCLC), RET-mutant medullary thyroid cancer, and RET fusion–positive thyroid cancer. Regulatory agencies are now evaluating pralsetinib for the same indications.

Onlookers have probed available data from phase I/II studies of selpercatinib and pralsetinib to divine substantive efficacy and toxicity differences between the two agents. Some have highlighted a potential safety advantage for pralsetinib; others have noted a higher overall response rate in the selpercatinib trial.

Without head-to-head trials, however, “there's really no good way to formally compare these—and it's early to make definitive cross-trial comparisons,” says Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, who led testing of selpercatinib.

Indeed, many oncologists suspect that the two RET inhibitors will prove largely interchangeable. “Clinically, both of these agents have produced very robust responses in both the treatment-naïve and the platinum-resistant patient populations, and they've also shown pretty impressive intracranial activity,” says Justin Gainor, MD, of Massachusetts General Hospital in Boston, who was involved in trials of both selpercatinib and pralsetinib.

Both drugs were generally well tolerated, with similar mechanisms of action and comparable vulnerabilities to resistance. Longer-term follow-up data could reveal some distinguishing clinical features, but broadly speaking, “I don't believe here we have major differences in terms of activity or safety,” says Giuseppe Curigliano, MD, PhD, of the European Institute of Oncology in Milan, Italy, who spearheaded trials of pralsetinib.

“Success,” Curigliano notes, “will be much more a marketing battle than a scientific battle because they are both very good agents.”

Roche, with its vast commercial network and diagnostic abilities, could thus help Blueprint overcome Lilly's first-to-market advantage. Currently, many patients with NSCLC are not routinely screened for RET alterations. Yet, with subsidiaries such as Foundation Medicine and Flatiron Health, Roche boasts an integrated genetic testing infrastructure that could prove invaluable for identifying those individuals whose tumors feature rare RET fusions or mutations.

“We now believe that Roche can drive pralsetinib to capture 50% of the RET market in non–small cell lung cancer,” analysts from SVB Leerink's targeted oncology team wrote in an investor note.

Under the terms of the agreement, Roche and Blueprint will jointly commercialize pralsetinib in the United States and equally share profits. Elsewhere, Roche will gain exclusive marketing rights and pay royalties to Blueprint—except in China, Hong Kong, Macau, and Taiwan, where CStone Pharmaceuticals has secured a licensing agreement. –Elie Dolgin

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