‘Immediately Practice-Changing’ Lung Cancer Trial in Curative Setting

CHICAGO — The adjuvant treatment of RET fusion-positive non-small-cell lung cancer (NSCLC) following potentially curative surgery or radiotherapy has a new standard of care, researchers reported here.

In a phase III study of patients who underwent definitive therapy for stage II-IIIA disease, event-free survival (EFS) at 2 years reached 92% with the oral RET inhibitor selpercatinib (Retevmo) versus 61% with placebo (HR 0.17, 95% CI 0.06-0.51, P<0.001), stated Jonathan Goldman, MD, of the University of California Los Angeles.

“The results are striking,” he said during a press briefing. “This amounts to an 83% reduction in the risk of cancer recurrence.”

The three deaths in the study, attributed to disease progression, were all in the placebo group, according to findings of the so-called LIBRETTO-432 study presented at the American Society of Clinical Oncology (ASCO) annual meeting and published simultaneously in the New England Journal of Medicine.

“These results highlight the importance of testing for specific gene changes at the time of diagnosis so that patients start on the most appropriate therapy from the beginning,” said Goldman.

‘New Standard of Care’

A major challenge in early-stage NSCLC is that despite potentially curative surgery or radiation, many patients remain at high risk of recurrence over the following 5 years, Goldman explained.

Positive adjuvant trials involving EGFR- or ALK-directed therapies have made it so it’s standard for patients with resected, early-stage NSCLCs driven by those alterations to receive targeted agents to try and cure them. But that benefit had yet to be demonstrated for the 1% to 2% of patients with NSCLCs driven by RET fusions, and many thought a similar trial in this rare population might be too difficult to conduct.

“This is a new standard of care,” said ASCO-designated expert David Spigel, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee. “If I have a patient in my clinic tomorrow who has early-stage disease that has a RET alteration, I absolutely would offer this therapy.”

In a statement, Spigel called the trial “immediately practice-changing.”

Goldman said that to enroll the 151 participants in the study, almost 3,500 were screened to identify those with RET mutations. That demonstrates the rarity of RET fusions, but also the need to screen patients early on.

“Rarity should not be mistaken for marginal importance,” he said.

Selpercatinib — an oral, highly potent, central nervous system-penetrant RET inhibitor — has already been approved for advanced RET-positive NSCLC and thyroid cancer and has an accelerated approval in the tumor agnostic setting for any solid cancer with a RET mutation.

Spigel, who was not involved with the research, called the study “groundbreaking” for patients with NSCLC driven by RET fusions, a group that disproportionately affects younger people with little or no smoking history.

LIBRETTO-432 Details

Goldman presented the primary analysis of LIBRETTO-432, a global, double-blind phase III trial involving 151 NSCLC patients who had received curative intent surgery or radiation for stage IB-IIIA disease, with adjuvant chemotherapy allowed. Participants were enrolled across 65 sites in 22 countries, and then randomized 1:1 to receive selpercatinib (twice daily, with dose depending on weight) or placebo for 3 years. Those in the placebo arm could crossover to receive selpercatinib at the time of disease recurrence or progression.

Among the 109 patients with stage II-IIIA disease in the primary analysis population, the median age was about 60 years, approximately 60% were women, and 69% were never-smokers. Most participants enrolled in East Asia while about a third enrolled in North America or Europe, and this was reflected in the demographics (61% Asian, 39% white). In terms of disease characteristics, a majority (57%) had stage IIIA disease, nearly all had undergone surgery, and the vast majority (over 90%) also received adjuvant chemotherapy.

The primary endpoint was investigator-assessed EFS in patients with stage II-IIIA disease. With a median follow-up of at least 24 months in each group, four EFS events (7%) occurred in the selpercatinib group as compared with 19 (35%) in the placebo group. Goldman said the EFS benefit was consistent across subgroups and confirmed on blinded independent review.

EFS results were largely similar in the overall study population that also included the 42 stage IB patients, with 2-year rates of 94% with adjuvant selpercatinib and 70% with placebo (HR 0.17, 95% CI 0.06-0.49, P<0.001).

Safety in the overall population was consistent with what has been observed in the metastatic setting, said Goldman. The most common adverse events (AEs) with selpercatinib included low-grade increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels.

Grade ≥3 AEs occurred in 67% of the selpercatinib arm and 24% of the placebo arm. Grade ≥3 ALT and AST increases (in 17% and 19%, respectively) resolved with dose modifications or drug holds, said Goldman.