A phase I/IB trial of the vegfr-sparing multikinase ret inhibitor RXDX-105

Alexander Drilon, Siqing Fu, Manish R. Patel, Marwan Fakih, Ding Wang, Anthony J. Olszanski, Daniel Morgensztern, Stephen V. Liu, Byoung Chul Cho, Lyudmila Bazhenova, Cristina P. Rodriguez, Robert C. Doebele, Antoinette Wozniak, Karen L. Reckamp, Tara Seery, Petros Nikolinakos, Zheyi Hu, Jennifer W. Oliver, Denise Trone, Katherine McArthurRupal Patel, Pratik S. Multani, Myung Ju Ahn

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

RET fusions are oncogenic drivers of various tumors, including non–small cell lung cancers (NSCLC). The safety and antitumor activity of the multikinase RET inhibitor RXDX-105 were explored in a phase I/Ib trial. A recommended phase II dose of 275 mg fed daily was identified. The most common treatment-related adverse events were fatigue (25%), diarrhea (24%), hypophosphatemia (18%), maculopapular rash (18%), and nonmaculopapular rash (17%). In the phase Ib cohort of RET inhibitor–naïve patients with RET fusion–positive NSCLCs, the objective response rate (ORR) was 19% (95% CI, 8%–38%, n = 6/31). Interestingly, the ORR varied significantly by the gene fusion partner (P < 0.001, Fisher exact test): 0% (95% CI, 0%–17%, n = 0/20) with KIF5B (the most common upstream partner for RET fusion–positive NSCLC), and 67% (95% CI, 30%–93%, n = 6/9) with non-KIF5B partners. The median duration of response in all RET fusion–positive NSCLCs was not reached (range, 5 to 18+ months). SIGNIFICANCE: Although KIF5B-RET is the most common RET fusion in NSCLCs, RET inhibition with RXDX-105 resulted in responses only in non– KIF5B–RET- containing cancers. Novel approaches to targeting KIF5B-RET- containing tumors are needed, along with a deeper understanding of the biology that underlies the differential responses observed.

Original languageEnglish
Pages (from-to)384-395
Number of pages12
JournalCancer Discovery
Volume9
Issue number3
DOIs
Publication statusPublished - 2019 Mar 1

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Exanthema
Non-Small Cell Lung Carcinoma
Hypophosphatemia
Neoplasms
Gene Fusion
Fatigue
Diarrhea
Safety
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Drilon, A., Fu, S., Patel, M. R., Fakih, M., Wang, D., Olszanski, A. J., ... Ahn, M. J. (2019). A phase I/IB trial of the vegfr-sparing multikinase ret inhibitor RXDX-105. Cancer Discovery, 9(3), 384-395. https://doi.org/10.1158/2159-8290.CD-18-0839
Drilon, Alexander ; Fu, Siqing ; Patel, Manish R. ; Fakih, Marwan ; Wang, Ding ; Olszanski, Anthony J. ; Morgensztern, Daniel ; Liu, Stephen V. ; Cho, Byoung Chul ; Bazhenova, Lyudmila ; Rodriguez, Cristina P. ; Doebele, Robert C. ; Wozniak, Antoinette ; Reckamp, Karen L. ; Seery, Tara ; Nikolinakos, Petros ; Hu, Zheyi ; Oliver, Jennifer W. ; Trone, Denise ; McArthur, Katherine ; Patel, Rupal ; Multani, Pratik S. ; Ahn, Myung Ju. / A phase I/IB trial of the vegfr-sparing multikinase ret inhibitor RXDX-105. In: Cancer Discovery. 2019 ; Vol. 9, No. 3. pp. 384-395.
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abstract = "RET fusions are oncogenic drivers of various tumors, including non–small cell lung cancers (NSCLC). The safety and antitumor activity of the multikinase RET inhibitor RXDX-105 were explored in a phase I/Ib trial. A recommended phase II dose of 275 mg fed daily was identified. The most common treatment-related adverse events were fatigue (25{\%}), diarrhea (24{\%}), hypophosphatemia (18{\%}), maculopapular rash (18{\%}), and nonmaculopapular rash (17{\%}). In the phase Ib cohort of RET inhibitor–na{\"i}ve patients with RET fusion–positive NSCLCs, the objective response rate (ORR) was 19{\%} (95{\%} CI, 8{\%}–38{\%}, n = 6/31). Interestingly, the ORR varied significantly by the gene fusion partner (P < 0.001, Fisher exact test): 0{\%} (95{\%} CI, 0{\%}–17{\%}, n = 0/20) with KIF5B (the most common upstream partner for RET fusion–positive NSCLC), and 67{\%} (95{\%} CI, 30{\%}–93{\%}, n = 6/9) with non-KIF5B partners. The median duration of response in all RET fusion–positive NSCLCs was not reached (range, 5 to 18+ months). SIGNIFICANCE: Although KIF5B-RET is the most common RET fusion in NSCLCs, RET inhibition with RXDX-105 resulted in responses only in non– KIF5B–RET- containing cancers. Novel approaches to targeting KIF5B-RET- containing tumors are needed, along with a deeper understanding of the biology that underlies the differential responses observed.",
author = "Alexander Drilon and Siqing Fu and Patel, {Manish R.} and Marwan Fakih and Ding Wang and Olszanski, {Anthony J.} and Daniel Morgensztern and Liu, {Stephen V.} and Cho, {Byoung Chul} and Lyudmila Bazhenova and Rodriguez, {Cristina P.} and Doebele, {Robert C.} and Antoinette Wozniak and Reckamp, {Karen L.} and Tara Seery and Petros Nikolinakos and Zheyi Hu and Oliver, {Jennifer W.} and Denise Trone and Katherine McArthur and Rupal Patel and Multani, {Pratik S.} and Ahn, {Myung Ju}",
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Drilon, A, Fu, S, Patel, MR, Fakih, M, Wang, D, Olszanski, AJ, Morgensztern, D, Liu, SV, Cho, BC, Bazhenova, L, Rodriguez, CP, Doebele, RC, Wozniak, A, Reckamp, KL, Seery, T, Nikolinakos, P, Hu, Z, Oliver, JW, Trone, D, McArthur, K, Patel, R, Multani, PS & Ahn, MJ 2019, 'A phase I/IB trial of the vegfr-sparing multikinase ret inhibitor RXDX-105', Cancer Discovery, vol. 9, no. 3, pp. 384-395. https://doi.org/10.1158/2159-8290.CD-18-0839

A phase I/IB trial of the vegfr-sparing multikinase ret inhibitor RXDX-105. / Drilon, Alexander; Fu, Siqing; Patel, Manish R.; Fakih, Marwan; Wang, Ding; Olszanski, Anthony J.; Morgensztern, Daniel; Liu, Stephen V.; Cho, Byoung Chul; Bazhenova, Lyudmila; Rodriguez, Cristina P.; Doebele, Robert C.; Wozniak, Antoinette; Reckamp, Karen L.; Seery, Tara; Nikolinakos, Petros; Hu, Zheyi; Oliver, Jennifer W.; Trone, Denise; McArthur, Katherine; Patel, Rupal; Multani, Pratik S.; Ahn, Myung Ju.

In: Cancer Discovery, Vol. 9, No. 3, 01.03.2019, p. 384-395.

Research output: Contribution to journalArticle

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T1 - A phase I/IB trial of the vegfr-sparing multikinase ret inhibitor RXDX-105

AU - Drilon, Alexander

AU - Fu, Siqing

AU - Patel, Manish R.

AU - Fakih, Marwan

AU - Wang, Ding

AU - Olszanski, Anthony J.

AU - Morgensztern, Daniel

AU - Liu, Stephen V.

AU - Cho, Byoung Chul

AU - Bazhenova, Lyudmila

AU - Rodriguez, Cristina P.

AU - Doebele, Robert C.

AU - Wozniak, Antoinette

AU - Reckamp, Karen L.

AU - Seery, Tara

AU - Nikolinakos, Petros

AU - Hu, Zheyi

AU - Oliver, Jennifer W.

AU - Trone, Denise

AU - McArthur, Katherine

AU - Patel, Rupal

AU - Multani, Pratik S.

AU - Ahn, Myung Ju

PY - 2019/3/1

Y1 - 2019/3/1

N2 - RET fusions are oncogenic drivers of various tumors, including non–small cell lung cancers (NSCLC). The safety and antitumor activity of the multikinase RET inhibitor RXDX-105 were explored in a phase I/Ib trial. A recommended phase II dose of 275 mg fed daily was identified. The most common treatment-related adverse events were fatigue (25%), diarrhea (24%), hypophosphatemia (18%), maculopapular rash (18%), and nonmaculopapular rash (17%). In the phase Ib cohort of RET inhibitor–naïve patients with RET fusion–positive NSCLCs, the objective response rate (ORR) was 19% (95% CI, 8%–38%, n = 6/31). Interestingly, the ORR varied significantly by the gene fusion partner (P < 0.001, Fisher exact test): 0% (95% CI, 0%–17%, n = 0/20) with KIF5B (the most common upstream partner for RET fusion–positive NSCLC), and 67% (95% CI, 30%–93%, n = 6/9) with non-KIF5B partners. The median duration of response in all RET fusion–positive NSCLCs was not reached (range, 5 to 18+ months). SIGNIFICANCE: Although KIF5B-RET is the most common RET fusion in NSCLCs, RET inhibition with RXDX-105 resulted in responses only in non– KIF5B–RET- containing cancers. Novel approaches to targeting KIF5B-RET- containing tumors are needed, along with a deeper understanding of the biology that underlies the differential responses observed.

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Drilon A, Fu S, Patel MR, Fakih M, Wang D, Olszanski AJ et al. A phase I/IB trial of the vegfr-sparing multikinase ret inhibitor RXDX-105. Cancer Discovery. 2019 Mar 1;9(3):384-395. https://doi.org/10.1158/2159-8290.CD-18-0839