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RET Inhibitor Selpercatinib Achieves Durable Responses in Majority of Patients With RET Gene Fusions


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For patients with non–small cell lung cancers (NSCLC) marked by RET gene fusions, the targeted therapy selpercatinib was well tolerated and achieved durable objective responses in the majority of participants in the phase I/II LIBRETTO-001 trial, according to researchers from The University of Texas MD Anderson Cancer Center.

The findings, published in The New England Journal of Medicine by Drilon et al, led to the U.S. Food and Drug Administration approval of selpercatinib in RET-altered lung and thyroid cancers.

Among previously untreated patients, the objective response rate (ORR) was 85%, and those receiving at least prior platinum-based chemotherapy had an ORR of 64%. For patients with brain metastases, there was a 91% ORR in the brain.

Unmet Need in RET Fusion–Positive NSCLC

“Genome-guided precision oncology has altered the landscape of multiple kinase-driven tumors, with lung cancer being the poster child. However, we previously did not have any drug approved specifically for RET fusion–positive non–small cell lung cancer,” said senior author Vivek Subbiah, MD, Associate Professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center. “Moving from the first-in-human phase I trial to FDA approval in less than 3 years is a testament to the fact that patients benefited a great deal from this treatment and had no effective options.”

RET fusions occur when a portion of the chromosome containing the RET gene breaks and rejoins with another piece of chromosome, creating a fusion protein capable of fueling cancer growth. RET alterations occur in roughly 2% of NSCLC, 10%–20% of papillary thyroid cancers, and the vast majority of medullary thyroid cancers. Up to half of all RET fusion–positive cancers metastasize to the brain.

Several targeted therapies, such as cabozantinib and vandetanib, have ancillary activity against RET alterations, but clinical trials found that NSCLC patients saw only limited benefit from these drugs, explained Dr. Subbiah, who is co-principal investigator of the trial.

Study Findings

The study reports findings from 144 patients with advanced NSCLC enrolled on the open-label, international trial. The primary endpoint was ORR assessed by an independent review committee, and secondary endpoints included safety, intracranial response, duration of response, and progression-free survival. Results from investigator assessments were not significantly different from that of independent reviewers.

KEY POINTS

  • The objective response rate was 85% among previously untreated patients and 64% among those receiving at least prior platinum-based chemotherapy.
  • Among patients with brain metastases, there was a 91% objective intracranial response.

The trial included 39 previously untreated patients and 105 patients who had received at least platinum-based chemotherapy. Previously treated patients had a median of three prior lines of therapy, including immune checkpoint blockade in more than half. Across both cohorts, trial participants were 57.6% White, 32.6% Asian, 5.6% Black, 2.8% other, and 1.4% unknown. The median age was 61, with women accounting for 58.3% and men 41.7% of participants.

Among previously treated patients, 2% had a complete response, 62% had a partial response and 29% had stable disease. The median duration of response was 17.5 months, and 63% of responses were ongoing at a median follow-up of 12 months. Median progression-free survival was 16.5 months.

In previously untreated patients, 85% had a partial response and 10% had stable disease. At 6 months, 90% of responses were ongoing, and neither median duration of response nor median progression-free survival has been reached at the time of analysis.

On the study, 11 patients had measurable brain metastases. Ten of these patients (91%) saw an objective response in the brain, including three complete responses. The median duration of central nervous system response was 10.1 months.

The most common adverse events of grade 3 or higher were hypertension (14%), increased aminotransferase (13%), increased aspartate aminotransferase (10%), hyponatremia (6%) and lymphopenia (6%). Four patients discontinued selpercatinib treatment due to treatment-related adverse events.

Strong Response Seen in Thyroid Cancer Cohort

In additional cohorts of LIBRETTO-001, selpercatinib also showed activity in RET-altered thyroid cancers, including medullary thyroid cancer with RET mutations and papillary/anaplastic thyroid cancers with RET fusions, with a similar safety profile.

Among patients with medullary thyroid cancer, there was a 73% ORR in previously untreated patients and 69% ORR in those receiving prior targeted therapies. In patients with previously treated papillary/anaplastic thyroid cancer, the ORR was 79%. These data also were published today in The New England Journal of Medicine, with Dr. Subbiah and Maria Cabanillas, MD, Professor of Endocrine Neoplasia and Hormonal Disorders, as co-senior authors.

“The data show these patients benefit from this treatment and it is safe compared with multikinase inhibitors and chemotherapy,” said Dr. Subbiah. “The continued implementation of a robust molecular screening strategy in frontline lung and thyroid cancers with the ability to detect RET and other gene fusions will be critical for identifying patients who may benefit from specifically targeted therapies like selpercatinib.”

Dr. Subbiah and Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, are co-corresponding authors of the New England Journal of Medicine article.

Disclosure: The study was supported by Loxo Oncology, a wholly owned subsidiary of Eli Lilly. For full disclosures of the study authors, visit www.nejm.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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