Hypersensitivity Reactions to Selpercatinib Treatment With or Without Prior Immune Checkpoint Inhibitor Therapy in Patients With NSCLC in LIBRETTO-001

Abstract

Introduction: Immune checkpoint inhibitor (ICI) therapy has been found to increase the risk/severity of immune-mediated adverse events with subsequent kinase inhibitor treatment in oncogenically driven cancers. We explored the risk for hypersensitivity with selpercatinib, a first-in-class highly selective and potent, central nervous system-active RET inhibitor, in prior ICI-treated patients with RET fusion-positive NSCLC compared with their ICI-naive counterparts.

Methods: Data from patients enrolled by December 16, 2019, in the ongoing phase 1/2 LIBRETTO-001 (NCT03157128) trial were analyzed for hypersensitivity reactions reported using preferred terms of hypersensitivity/drug hypersensitivity and defined as a constellation of symptoms/findings characterized by maculopapular rash, often preceded by fever with arthralgias/myalgias, followed by greater than or equal to 1 of the following signs/symptoms: thrombocytopenia, increased aspartate aminotransferase or alanine aminotransferase, hypotension, tachycardia, or increased creatinine.

Results: Of 329 patients, 22 (7%) who experienced a grade 1 to 3 hypersensitivity reaction that met the defined constellation of events were attributed to selpercatinib by investigators, and more often in prior ICI-treated (n = 17, 77%) than ICI-naive (n = 5, 23%) patients. There were 19 patients with selpercatinib-related hypersensitivity who resumed selpercatinib post-hypersensitivity with dose modification/supportive care. Furthermore, 17 patients, of whom 14 received prior ICI therapy, were still on treatment at twice daily doses of 40 mg (n = 5), 80 mg (n = 4), 120 mg (n = 4), and 160 mg (n = 4).

Conclusions: Rates of selpercatinib-related hypersensitivity were low overall and, as with other kinase inhibitors, occurred predominantly in prior ICI-treated patients. Hypersensitivity to selpercatinib can be managed with supportive care measures regardless of prior ICI status and is reversible.

Keywords: Hypersensitivity; Immune checkpoint inhibitor; Non–small-cell lung cancer; Selpercatinib; Supportive care.

Figure 1.

Treatment duration, dose modifications, and best overall response assessed by IRC with selpercatinib in patients with RET fusion-positive NSCLC who experienced a drug-related hypersensitivity reaction (N = 22). All patients began selpercatinib treatment on the recommended phase 2 dose of 160 mg twice daily. Best overall responses assessed by the IRC by data cutoff date of December 16, 2019, are presented. ^aThe patient permanently discontinued treatment with the first recurrence of hypersensitivity (grade 2) on rechallenge with a dose of 120 mg. ^bThe patient permanently discontinued treatment with the first event of hypersensitivity (grade 3) diagnosed 5 days after selpercatinib was discontinued. ^cThe patient permanently discontinued treatment with the first event of hypersensitivity (grade 2). ICI, immune checkpoint inhibitor; IRC, independent review committee; RP2D, recommended phase 2 dose.

Figure 2.

Guidelines for the management of selpercatinib-induced drug hypersensitivity. CBC, complete blood count; CMP, comprehensive metabolic panel; IL-6, interleukin-6; CRP, C-reactive protein.

Figure 3.

(A) An illustrative example of selpercatinib hypersensitivity. A 52-year-old white female, never smoker, with a stage IV NSCLC harboring a KIF5B-RET fusion. Selpercatinib was initiated as fourth-line therapy about 5 months after ICI therapy was discontinued. On C1D8 of selpercatinib 160 mg twice daily, she presented with grade 2 diarrhea (ultimately, results were negative for both Clostridium difficile and complete stool cultures), grade 1 fever (temperature of 37.4^◦C) for 2 days, and grade 3 diffuse cutaneous rash. She was treated with ibuprofen, acetaminophen, and topical steroids, and the fever resolved. She also underwent punch skin biopsy (B), which revealed spongiotic dermatitis, superficial perivascular lymphocytic infiltrate, rare eosinophils, and pigment incontinence that favored drug reaction. Laboratory results revealed thrombocytopenia (nadir of 60th/μL[60 × 10⁹/liter]) and elevated creatinine (up to 2.07 mg/dL [182.99 μmol/liter]). Selpercatinib was held and prednisone 60 mg daily was initiated. Diarrhea and rash resolved after 48 h. Selpercatinib was resumed at 40 mg twice daily on C1D22 while continuing steroid therapy. The dose was sequentially escalated weekly to 80 mg twice daily, 120 mg twice daily, and then to the original starting dose of 160 mg twice daily. The patient achieved a partial response by RECIST 1.1 for 19 cycles of selpercatinib before developing progressive disease. Image was created with Biorender.com. (B) Skin pathology of selpercatinib hypersensitivity reaction. Histology of the erythematous eruption on the right side of the chest depicts skin with diffuse epidermal spongiosis/edema, perivascular lymphocytic inflammation (example within black box), and pigment incontinence (black arrows). Rare eosinophils are identified (white arrow). Image courtesy of Linda Huijie Song, MD, MSPH; University of Maryland, Department of Pathology. C1D22, cycle 1 day 22; CID8, cycle 1 day 8; h, hour; ICI, immune checkpoint inhibitor; RECIST 1.1, Response Evaluation Criteria in Solid Tumors version 1.1.