RET Inhibitor Posts Frontline Wins in Medullary Thyroid Cancer, NSCLC

MADRID — First-line treatment with the RET inhibitor selpercatinib (Retevmo) achieved superior outcomes in both medullary thyroid cancer (MTC) and advanced non-small cell lung cancer (NSCLC), according to results from two phase III trials presented here.

In the LIBRETTO-531 trial, selpercatinib resulted in superior progression-free survival (PFS) and treatment failure-free survival (TFFS) compared with the multikinase inhibitors cabozantinib (Cabometyx) or vandetanib (Caprelsa) in patients with RET-mutant MTC, reported Julien Hadoux, MD, PhD, of Gustave Roussy in Villejuif, France, at the annual congress of the European Society for Medical Oncology (ESMO).

At a median follow-up of 12 months, median PFS was not reached in the selpercatinib group compared with 16.8 months in the control group (HR 0.28, 95% CI 0.16-0.48, P<0.001). Median TFFS was not reached in the selpercatinib group versus 13.9 months in the control group (HR 0.25, 95% CI 0.15-0.42, P<0.001).

“These results support selpercatinib as the first-line standard of care for patients with advanced RET-mutant MTC,” Hadoux said, adding that the study “highlights the importance of RET selectivity when treating patients, and biomarker testing for patients with resectable MTC.”

This a “practice-changing trial,” said ASCO discussant Laura Locati, MD, PhD, of the Istituto Nazionale dei Tumori in Milan. “This is a very rare cancer — less than 5% of patients with thyroid cancer — and RET in medullary is present in about 89% of those patients with metastatic disease. With selpercatinib we have, for the first time, a very active treatment in terms of response rate, and prolonged response, and very few side effects compared to the standard of care, which are multikinase inhibitors.”

Meanwhile, results from the LIBRETTO-431 trial showed that treatment with selpercatinib more than doubled PFS compared with platinum-based chemotherapy with or without pembrolizumab (Keytruda) among patients with advanced RET fusion-positive NSCLC.

Median PFS reached 24.8 months with selpercatinib versus 11.2 months in the control group where physician’s intended to treat with chemotherapy plus pembrolizumab (HR 0.46, 95% CI 0.31-0.70, P<0.001), reported Herbert H. Loong, MBBS, of the Chinese University of Hong Kong.

“Selpercatinib should be considered as a first-line standard of care in RET fusion-positive advanced non-small cell lung cancer,” he said, and echoed Hadoux’s observation that the results reinforce the importance of genomic testing — in this case in order to identify RET fusions at the time of diagnosis to help guide initial therapy.

Both the MTC and NSCLC trial results were published simultaneously in the New England Journal of Medicine.

MTC Study Details

Multikinase inhibitors cabozantinib and vandetanib have been established as standard of care for first-line treatment of advanced MTC. However, “these have suboptimal RET inhibition potency, and a safety profile that requires frequent dose reduction and treatment discontinuation,” Hadoux observed.

In LIBRETTO-531, 291 patients who had not previously received a kinase inhibitor for the treatment of advanced or metastatic disease were enrolled at 176 centers in 19 countries, with 193 randomly assigned to the selpercatinib group and 98 to the control group (73 patients receiving cabozantinib and 25 vandetanib). Most patients were male, and the median age was 56 in the selpercatinib arm and 54 in the control arm.

In the selpercatinib group, 12-month PFS was 86.8% versus 65.7% in the control group, while 12-month TFFS was 86.2% and 62.1%, respectively.

A total of 69.4% of patients responded to selpercatinib, as compared with 38.8% of those in the control group, including complete responses in 11.9% and 4.1%, respectively.

Locati called the response rate with selpercatinib “remarkable,” and said it raised the question of cure and how long patients needed to be treated after obtaining a complete clinical remission.

Regarding overall survival (OS), at a median follow-up of 15 months, 94.8% of patients in the selpercatinib arm were still alive versus 85.7% in the control arm, but OS results were not mature at the time of this analysis.

Adverse events led to a dose reduction in 38.9% of patients in the selpercatinib group, compared with 77.3% in the control group, and to treatment discontinuation in 4.7% and 26.8%, respectively.

NSCLC Study Details

LIBRETTO-431 included 261 patients in the overall intention-to-treat (ITT) population, 212 of whom were in the ITT-pembrolizumab population (patients whose physicians planned to treat them with pembrolizumab in the event that they were assigned to the control group). Of those, 129 were assigned to receive selpercatinib and 83 received standard of care chemotherapy plus pembrolizumab. The majority of the patients were women, younger than 65 years of age, and never smokers.

The primary endpoint was PFS assessed by blinded independent central review in both the ITT-pembrolizumab population and the overall ITT population.

PFS results for the overall ITT population were essentially identical, at 24.8 months for patients assigned to selpercatinib versus 11.2 months for those receiving chemotherapy with or without pembrolizumab (HR 0.48, 95% CI 0.33-0.70, P<0.001).

ASCO discussant Benjamin Besse, MD, PhD, of the Gustave Roussy in Villejuif, France, noted that the control arms in both ITT populations was “strictly the same — 11.2 months, with the same confidence interval, suggesting that immunotherapy does not add a lot in this population.”

Loong reported the overall response rate (ORR) was higher, and more durable with selpercatinib (ORR of 83.7%, with a median duration of response of 24.2 months vs 65.1% and 11.5 months with control treatment).

Among patients with measurable brain metastases at baseline, intracranial outcomes for the selpercatinib group versus the control group were:

• Intracranial ORR: 82.4% vs 58.3%
• Complete response rates: 35.3% vs 16.7%
• 12-month duration of intracranial response rate: 76.0% vs 62.5%
• Median PFS: 16.1 months vs 10.4 months

The 12-month cumulative incidence rate of developing brain metastases was 5.5% with selpercatinib versus 20.3% in the control group.

“What is particularly of interest is the fact that in the patients who did not have CNS metastases at baseline, the 12-month cumulative incidence rate of the presence of CNS progression was only 1.1% [with selpercatinib] as opposed to 14.7% in the control group,” Loong pointed out. “With this data in mind I think it is reasonable to say that not only is selpercatinib active in patients who have brain metastases, but there is evidence of a preventive effect of development of brain metastases in patients in RET fusion non-small cell lung cancer.”

OS data were immature at the time of the analysis.

The most common adverse events associated with selpercatinib included aspartate aminotransferase and alanine aminotransferase increases, hypertension, diarrhea, and edema, “and these are consistent with what we’ve seen in prior clinical trials,” Loong said.

Besse observed that while the trial results were highly positive and certainly “good news,” the FDA has already granted regular approval to selpercatinib for adults with locally advanced or metastatic NSCLC with a RET gene fusion, based on robust results from LIBRETTO-001.

He noted that while European regulators have given conditional approval to the drug, confirmatory data from a randomized trial was needed. However, the results from LIBRETTO-431 were “so expected that it put into question the need to put patients into a study arm that did not receive a highly effective drug,” Besse said. “It’s unnecessary.”

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