Selpercatinib Induces Infrequent Hypersensitivity in RET Fusion-Positive NSCLC, Analysis Shows

Selpercatinib (LOXO-292)-related hypersensitivity reactions occurred infrequently in patients with RET fusion-positive non–small cell lung cancer (NSCLC), with more cases reported in patients previously treated with an immune checkpoint inhibitor (ICI), but reactions were deemed manageable with recommended guidance and supportive care, according to findings from an subset analysis of the phase 1/2 LIBRETTO-001 study (NCT03157128).

The first-in-class selective RET inhibitor received its approval from the FDA for the treatment of patients with metastatic RET fusion-positive NSCLC based on the findings from the ongoing global multicenter LIBRETTO-001 study. The trial demonstrated remarkable efficacy and safety with selpercatinib in this patient population regardless of previous treatments. There was notable activity observed in the frontline setting as well, but rare hypersensitivity reactions were also observed in the trial, particularly among patients with RET fusion-positive NSCLC who were previously treated with ICI therapy.

In a larger safety dataset, an analysis explored hypersensitivity reactions to selpercatinib as treatment of patients with RET fusion-positive NSCLC in the ongoing LIBRETTO-001 study. Investigators also assessed responses to treatment by subgroups of patients with or without prior ICI therapy.

The adverse events (AEs) of 329 patients were assessed in a custom safety clustering analysis to identify and evaluate hypersensitivity reaction, which was defined as a constellation of events occurring in the initial weeks of treatment presenting as maculopapular rash, often preceded by fever with associated arthralgias or myalgias, followed by either thrombocytopenia or aspartate aminotransferase/alanine transaminase (AST/ALT) increase, which are the most common, and/or the less common signs and symptoms, decreased blood pressure, tachycardia, and/or creatine increase.

The median age of patients on the study was 61 (range, 23-92). The majority of patients were female (185 patients; 56.2%) and White (165; 50.2%) or Asian (136; 41.3%). The median duration of metastatic disease at enrollment was 12 months (range, 0.0-127.4). Overall, 166 (50.5%) had received prior radiotherapy, and 140 (42.6%) had received prior surgery. The number of prior systemic therapies was 0 in 60 patients (18.2%), 1-2 in 157 (47.8%), and 3 or more in 112 (34.0%). One-hundred fifty-two (46.2%) had received prior ICI therapy.

Treatment-emergent AEs (TEAEs) of hypersensitivity of any grade occurred in 25 (7.6%) of patients in the overall safety population, including 19 (12.5%) in the prior ICI therapy arm and 6 (3.4%) in the ICI-naïve arm, and grade 3 TEAEs of hypersensitivity occurred in 9 (2.7%) overall, 5 (3.3%) and 4 (2.3%), respectively. Serious TEAEs of hypersensitivity occurred in 8 patients (5.3%) in the prior ICI therapy arm and 4 (2.3%) in the ICI-naïve arm, occurring in 12 (3.6%) overall.

TEAEs of hypersensitivity related to selpercatinib of any grade occurred in 17 (11.2%) of the prior ICI therapy arm versus 5 (2.8%) in the ICI-naïve arm, and serious TEAEs of hypersensitivity related to the drug occurred in 8 (5.3%) versus 4 (2.3%), respectively.

Although patients pretreated with ICI therapy appeared to be at an increased risk of hypersensitivity, the overall safety and tolerability of selpercatinib in this patient population was not impacted, while most patients were able to continue receiving treatment.

Overall, 18 patients (5.5%) required a dose reduction, 6 (1.8%) an interruption, and 3 (0.9%) treatment discontinuation. The majority of dose modifications occurred in the prior ICI therapy arm, whereas 14 patients (9.2%) had a reduction, 4 (2.6%) had an interruption, and 2 (1.3%) discontinued treatment.

The median time to first onset of hypersensitivity was 1.7 weeks (range, 1.0-15.6) in the prior ICI therapy arm and 2.4 weeks (range, 0.9-22.1) in the ICI-naïve arm. In terms of outcomes of last episodes, 17 patients (11.2%) in the prior ICI therapy arm versus 5 (2.8%) in the ICI-naïve arm had recovered/resolved, 1 (0.7%) versus 0 were recovering/resolving, and 1 (0.7%) versus 1 (0.6%) were not recovered/not resolved.

The most common grade 3 or higher TEAEs in the prior ICI therapy arm, occurring in at least 20% or more, included hypertension (15.1%), ALT increase (13.8%), AST increase (12.5%), and thrombocytopenia (5.9%). In the overall population, the most common grade 3 or higher included hypertension (16.7%), ALT increase (11.2%), AST increase 28 (8.5%), thrombocytopenia (4.9%), and diarrhea (2.7%).

The incidence of hypersensitivity, overall, was low, and did not result in anaphylaxis or fatal outcomes overall, and mostly appeared as cases of grades 1 or 2 in severity. Most patients who had experienced selpercatinib-induced hypersensitivity were able to successfully continue selpercatinib treatment with dose modifications and steroids. The recommendations for managing these events include withholding selpercatinib until resolution and initiate corticosteroids, resume selpercatinib at a reduced dose by 3 dose levels while continuing corticosteroids, and increase selpercatinib dose by 1 dose level each week until the dose taken prior to hypersensitivity onset is reached, then taper corticosteroid use.

Selpercatinib-induced hypersensitivity recurred in some patients within 3 to 6 hours following administration of the drug. The recommendations for managing recurrence of reactions, if the recurrence is severe, includes holing selpercatinib with repeat management as previously noted and target dose adjusted to 1 dose level before that at which recurrence occurred. If the recurrence is clinically significant at the initial re-exposure dose, selpercatinib should be discontinued, but in the absence of a clinically significant recurrent hypersensitivity, after a minimum of 7 days on re-exposure dose, the dose may be escalated sequentially. If the patient tolerated treatment for at least 7 days at the final dose, steroids may be tapered slowly. In the event of a mild recurrence, patients can cautiously continue selpercatinib with supportive care, such as topical treatments or ibuprofen.

Tumor responses were also evaluated by subgroups of patients with or without prior ICI therapy. The primary analysis set used for this analysis included 105 pretreated patients with platinum-based chemotherapy and 39 patients who were treatment-naïve.

The overall response rate (ORR) among patients pretreated with platinum chemotherapy was 66% (95% CI, 51.9-77.5) in those who received prior ICI versus 62% (95% CI, 46.4-75.5) in those who were ICI-naïve, whereas complete responses were observed in 1(1.7%) versus 1 (2.1%), partial responses (PRs) in 37 (63.8%) versus 28 (59.6%), stable disease (SD) in 13 (22.4%) versus 17 (36.2%), and progressive disease (PD) in 3 (5.2%) versus 1 (2.1). Four patients in the prior ICI therapy arm were not evaluable (6.9%).

The responses to selpercatinib were meaningful and durable, regardless of prior chemotherapy or ICI therapy; responses appeared best in those who were treatment-naïve, however with an ORR of 85% (95% CI, 69.5-94.1), which included PRs in 33 (84.6%) of patients, SD in 4 (10.3%), and PD in 1 (2.6%), while 1 patient (2.6%) was not evaluable.

For patients with NSCLC, treatment sequencing decisions should include the consideration of the possible limited utility of ICI therapy and the potential for increased frequency and/or severity of immune-mediated toxicities in those receiving targeted therapy after prior ICI therapy, according to Caroline Coach et al. The ongoing phase 3 LIBRETTO-431 clinical trial (NCT04194944) is currently evaluating frontline selpercatinib compared with chemoimmunotherapy in patients with advanced or metastatic RET fusion-positive NSCLC.

_Reference

_{McCoach C, Tan DSW, Besse B, et al. Hypersensitivity reactions to selpercatinib in patients with RETfusion-positive non-small cell lung cancer (NSCLC). Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract P1054.}