About 15 months after closing its multibillion-dollar acquisition of Loxo Oncology Inc., Eli Lilly and Co. has secured an accelerated FDA approval for the first of the deal's headline assets, the RET kinase inhibitor selpercatinib, now branded as Retevmo. The green light, following a priority review, allows for marketing of the drug as a treatment for three types of tumors – non-small-cell lung cancer (NSCLC), medullary thyroid cancer (MTC) and other types of thyroid cancers – in patients whose tumors have a rearranged during transfection (RET) alteration. The decision arrived well ahead of an earlier-projected third-quarter decision by the agency.

Retevmo, earlier granted FDA breakthrough status, is the first therapy approved specifically for cancer patients with the RET gene alterations, though Blueprint Medicines Corp. has pursued similar indications to Lilly for its own RET inhibitor, pralsetinib.

Retevmo's list price will be about $20,600 per 30 days of therapy, which Lilly said is generally in line with other oral targeted therapies. Out-of-pocket costs will, of course, vary based on insurance plan benefit designs. The company is working to make the new medicine available within one week.

"Innovations in gene-specific therapies continue to advance the practice of medicine at a rapid pace and offer options to patients who previously had few," said Richard Pazdur, director of the FDA's Oncology Center of Excellence and acting director of its Office of Oncologic Diseases. The agency “is committed to reviewing treatments like Retevmo that are targeted to specific subsets of patients with cancer,” he said.

RET fusions and mutations occur across multiple tumor types with varying frequency. RET fusions, or translocations that bring two different genes together, are found in about 2% of NSCLC cases and about 10% to 20% of thyroid cancers. Activating point mutations, on the other hand, are more common, showing up in about 60% of sporadic MTCs and about 90% of germline MTCs.

"Developing selective inhibitors that turn off these driver genomic alterations really leads to highly effective treatments with good tolerability," Maura Dickler, vice president of late phase development for Lilly oncology, told BioWorld. With the advent of medicines targeting EGFR, ALK rearrangements and ROS1, the next-generation sequencing (NGS) of tumors that supports the approach has become increasingly common.

As scientists have become better at identifying underlying genomic alterations that drive cancers, they're better able to design drugs that more potently inhibit the aberrant proteins that come from those alterations, she said. "When we're identifying the right patient and giving the right drug, we now see high response rates that last for much longer than for what previous chemotherapy had done in the past," she said.

Still, identifying the right patients for Retevmo is likely to require some concerted effort on Lilly's part to encourage more biomarker testing. Though such testing is becoming increasingly common in lung cancer, with 30% to 40% of patients tested today, "we need to drive that up so that we know that patients get the right medicine," Lilly Oncology President Anne White told BioWorld.

Accordingly, out the gate, a big part of Lilly's communications plan for Retevmo will be to encourage doctors and patients to have NGS done. For Medicare and Medicaid patients, the costs of such testing is already reimbursed. Reimbursement from commercial insurers is more varied, with some just looking for biomarkers one at a time. Lilly will also work to encourage broader use of NGS panels that test for multiple actionable mutations at once, she said. "If they do testing one at a time, that can obviously take a while. And sometimes there's not even enough tissue that's been pulled from the patient to do multiple biomarker tests," she said.

Retevmo was designed to inhibit native RET signaling as well as anticipated acquired resistance mechanisms. Its approval was founded on data from the Loxo-initiated phase I/II LIBRETTO-001 study, the largest clinical trial ever conducted in RET-altered lung and thyroid cancers, according to Lilly.

Patients enrolled in the trial received 160-mg Retevmo orally twice daily until disease progression or unacceptable toxicity. The major efficacy outcome measures were overall response rate (ORR), which reflects the percentage of patients that had a certain amount of tumor shrinkage, and duration of response (DOR).

According to the FDA, efficacy for NSCLC was evaluated in 105 adults with RET fusion-positive NSCLC who were previously treated with platinum chemotherapy. The ORR for the 105 patients was 64%. For 81% of patients who had a response, their response lasted at least six months. Efficacy was also evaluated in 39 patients with RET fusion-positive NSCLC who had never undergone treatment. The ORR for those patients was 84%. For 58% of patients who had a response to the treatment, their response also lasted at least six months.

The study also enrolled 143 patients with advanced or metastatic RET-mutant MTC who had been previously treated with cabozantinib, vandetanib or both, and patients with advanced or metastatic RET-mutant MTC who had not received prior treatment with either of those chemotherapies. The ORR for the 55 previously treated patients was 69%. For 76% of patients who had a response to the treatment, their response lasted at least six months. Efficacy was also evaluated in 88 patients who had not been previously treated with an approved therapy for MTC. The ORR for those patients was 73%. For 61% of patients who had a response to the treatment, their response lasted at least six months.

Finally, the study also enrolled 19 patients with RET fusion-positive thyroid cancer who were radioactive iodine (RAI)-refractory and had received another prior systemic treatment, and eight patients with RET fusion-positive thyroid cancer who were RAI-refractory and had not received any additional therapy. The ORR for the 19 previously treated patients was 79%. For 87% of patients who had a response to the treatment, their response lasted at least six months. Efficacy was also evaluated in eight patients who had not received therapy other than RAI. The ORR for those patients was 100%. For 75% of patients who had a response to the treatment, their response lasted at least six months.

Despite those benefits, Retevmo can cause serious side effects, including liver damage or injury, elevated blood pressure, QT prolongation, bleeding and allergic reactions. Other side effects, such as decreased white blood cell counts and decreased amounts of albumin and calcium in the blood, were among the most common.

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