Phase 1 multicenter study of the HSP90 inhibitor SNX-5422 plus carboplatin and paclitaxel in patients with lung cancers

Martin Gutierrez; Robin Guo; Giuseppe Giaccone; Stephen V. Liu; Zhonglin Hao; Christie Hilton; James M. Hinson; Mark G. Kris; Everardus Otto Orlemans; Alexander Drilon

doi:10.1016/j.lungcan.2021.10.001

Phase 1 multicenter study of the HSP90 inhibitor SNX-5422 plus carboplatin and paclitaxel in patients with lung cancers

Martin Gutierrez, Robin Guo, Giuseppe Giaccone, Stephen V. Liu, Zhonglin Hao, Christie Hilton, James M. Hinson, Mark G. Kris, Everardus Otto Orlemans, Alexander Drilon

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

Objectives: Single-agent heat shock protein 90 (HSP90) inhibition has demonstrated activity in oncogene-driven non-small cell and small cell lung cancers. SNX-5422 is an oral HSP90 inhibitor with increased activity in vitro with the addition of carboplatin and paclitaxel. Therefore, we conducted a phase 1, open-label, multicenter study to evaluate SNX-5422, carboplatin and paclitaxel followed by SNX-5422 maintenance in patients with advanced lung cancers. Materials and methods: In part 1 (3 + 3 dose escalation), SNX-5422 (50/75/100-mg/m²) was dosed every other day (qod) for 21 days (28-day cycle) for ≤4 cycles; carboplatin (AUC 5)-paclitaxel (175 mg/m²) was administered once every 3 weeks for ≤6 courses. In part 2 (maintenance), subjects who achieved at least stable disease in part 1 received 100 mg/m² SNX-5422 monotherapy qod for 21 days (28-day cycle). Results: Twenty-three patients with advanced non-small cell lung cancer (NSCLC, n = 20) and small cell lung cancer (SCLC, n = 3) were enrolled. The median age was 60 years and 61% (n = 14/23) had ≥1 prior treatment regimens. The maximum tolerated dose of SNX-5422 was 100 mg/m² qod in combination with carboplatin-paclitaxel. The most common treatment-related grade 3/4 adverse events (part 1/part 2) were diarrhea (26%/15%) and nausea (9%/0%). In response-evaluable patients with NSCLC, 33% (6/18) had a partial response, 56% (10/18) stable disease, and 11% (2/18) progressive disease. Patients who remained on single-agent SNX-5422 maintenance therapy ≥2 months (n = 9) had cancers enriched for oncogenic drivers (n = 3 KRAS mutation, n = 1 EGFR exon 20 mutation, n = 1 HER2 mutation, and n = 1 RET fusion). Conclusions: The triplet combination of SNX-5422, carboplatin and paclitaxel followed by maintenance SNX-5422 therapy was well-tolerated and showed anti-tumor activity. Cancers for which disease control on single-agent SNX-5422 maintenance was observed were enriched for oncogene-driven NSCLCs.

Original language	English
Pages (from-to)	23-28
Number of pages	6
Journal	Lung Cancer
Volume	162
DOIs	https://doi.org/10.1016/j.lungcan.2021.10.001
State	Published - Dec 2021

Bibliographical note

Publisher Copyright:
© 2021

Funding

This work was supported by Esanex, Inc. The sponsor had a role in the study design, in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. This study was partially supported by a National Cancer Institute Cancer Center grant to Memorial Sloan Kettering Cancer Center ( P30 CA008748 ). R.G. declares honoraria from Pfizer. G.G. declares no conflicts. S.V.L. declares Advisory Board/Consultant: Amgen, AstraZeneca, Bayer, Beigene, Blueprint, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Elevation Oncology, Genentech/Roche, Guardant Health, Janssen, Jazz Pharmaceuticals, Lilly, Merck/MSD, Novartis, Regeneron, Sanofi, Takeda, Turning Point Therapeutics. Research grant (to institution): Alkermes, Bayer, Blueprint, Bristol-Myers Squibb, Elevation Oncology, Genentech, Lilly, Merck, Merus, Pfizer, Rain Therapeutics, RAPT, Turning Point Therapeutics. C.H. has served as a speaker for AstraZeneca and Daiichi-Sankyo and has acted as a consultant for JHU partners in the metastatic breast cancer program. M.G.K. receives personal fees from Novartis, Sanofi-Genzyme, AstraZeneca, Pfizer, Janssen, and Daiichi-Sankyo; received honoraria for participation in educational programs from WebMD, OncLive, Physicians Education Resources, Prime Oncology, Intellisphere, Creative Educational Concepts, Peerview, i3 Health, Paradigm Medical Communications, AXIS, Carvive Systems, and AstraZeneca; received travel support from AstraZeneca, Pfizer, and Genentech; received editorial support from Hoffman La-Roche. Memorial Sloan Kettering has received research funding from The National Cancer Institute (USA), The Lung Cancer Research Foundation and Genentech Roche for research conducted by Dr. Kris. E.O.O. is an employee of Esanex, Inc. and owns stock in Esanex. A.D. declares: Honoraria/Advisory Boards: Ignyta/Genentech/Roche, Loxo/Bayer/Lilly, Takeda/Ariad/Millenium, TP Therapeutics, AstraZeneca, Pfizer, Blueprint Medicines, Helsinn, Beigene, BergenBio, Hengrui Therapeutics, Exelixis, Tyra Biosciences, Verastem, MORE Health, Abbvie, 14ner/Elevation Oncology, Remedica Ltd., ArcherDX, Monopteros, Novartis, EMD Serono, Melendi, Liberum, Repare RX; Associated Research Paid To Institution: Pfizer, Exelixis, GlaxoSmithKline, Teva, Taiho, PharmaMar; Royalties: Wolters Kluwer; Other: Merck, Puma, Merus, Boehringer Ingelheim; CME Honoraria: Medscape, OncLive, PeerVoice, Physicians Education Resources, Targeted Oncology, Research to Practice, Axis, Peerview Institute, Paradigm Medical Communications, WebMD, MJH Life Sciences. The authors thank the participating patients and their families. Medical writing support was provided by Lorraine R. Baer, PharmD (Baer PharMed Consulting, Ltd.), and was funded by Esanex Inc.

Funders	Funder number
Esanex Inc
Esanex, Inc.
Roche Genentech
F. Hoffman-La Roche Ltd
National Cancer Institute Cancer Nanotechnology Training Center	P30 CA008748
National Childhood Cancer Registry – National Cancer Institute	P30CA008748
Pfizer
AstraZeneca
Lung Cancer Research Foundation

Keywords

EGFR wild-type
HSP90 inhibitor
NSCLC
Platinum therapy
SNX-5422

ASJC Scopus subject areas

Oncology
Pulmonary and Respiratory Medicine
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.lungcan.2021.10.001

Cite this

@article{3f11bfe3140b4b34b52fd8867262fcc8,

title = "Phase 1 multicenter study of the HSP90 inhibitor SNX-5422 plus carboplatin and paclitaxel in patients with lung cancers",

abstract = "Objectives: Single-agent heat shock protein 90 (HSP90) inhibition has demonstrated activity in oncogene-driven non-small cell and small cell lung cancers. SNX-5422 is an oral HSP90 inhibitor with increased activity in vitro with the addition of carboplatin and paclitaxel. Therefore, we conducted a phase 1, open-label, multicenter study to evaluate SNX-5422, carboplatin and paclitaxel followed by SNX-5422 maintenance in patients with advanced lung cancers. Materials and methods: In part 1 (3 + 3 dose escalation), SNX-5422 (50/75/100-mg/m2) was dosed every other day (qod) for 21 days (28-day cycle) for ≤4 cycles; carboplatin (AUC 5)-paclitaxel (175 mg/m2) was administered once every 3 weeks for ≤6 courses. In part 2 (maintenance), subjects who achieved at least stable disease in part 1 received 100 mg/m2 SNX-5422 monotherapy qod for 21 days (28-day cycle). Results: Twenty-three patients with advanced non-small cell lung cancer (NSCLC, n = 20) and small cell lung cancer (SCLC, n = 3) were enrolled. The median age was 60 years and 61\% (n = 14/23) had ≥1 prior treatment regimens. The maximum tolerated dose of SNX-5422 was 100 mg/m2 qod in combination with carboplatin-paclitaxel. The most common treatment-related grade 3/4 adverse events (part 1/part 2) were diarrhea (26\%/15\%) and nausea (9\%/0\%). In response-evaluable patients with NSCLC, 33\% (6/18) had a partial response, 56\% (10/18) stable disease, and 11\% (2/18) progressive disease. Patients who remained on single-agent SNX-5422 maintenance therapy ≥2 months (n = 9) had cancers enriched for oncogenic drivers (n = 3 KRAS mutation, n = 1 EGFR exon 20 mutation, n = 1 HER2 mutation, and n = 1 RET fusion). Conclusions: The triplet combination of SNX-5422, carboplatin and paclitaxel followed by maintenance SNX-5422 therapy was well-tolerated and showed anti-tumor activity. Cancers for which disease control on single-agent SNX-5422 maintenance was observed were enriched for oncogene-driven NSCLCs.",

keywords = "EGFR wild-type, HSP90 inhibitor, NSCLC, Platinum therapy, SNX-5422",

author = "Martin Gutierrez and Robin Guo and Giuseppe Giaccone and Liu, \{Stephen V.\} and Zhonglin Hao and Christie Hilton and Hinson, \{James M.\} and Kris, \{Mark G.\} and Orlemans, \{Everardus Otto\} and Alexander Drilon",

note = "Publisher Copyright: {\textcopyright} 2021",

year = "2021",

month = dec,

doi = "10.1016/j.lungcan.2021.10.001",

language = "English",

volume = "162",

pages = "23--28",

}

TY - JOUR

T1 - Phase 1 multicenter study of the HSP90 inhibitor SNX-5422 plus carboplatin and paclitaxel in patients with lung cancers

AU - Gutierrez, Martin

AU - Guo, Robin

AU - Giaccone, Giuseppe

AU - Liu, Stephen V.

AU - Hao, Zhonglin

AU - Hilton, Christie

AU - Hinson, James M.

AU - Kris, Mark G.

AU - Orlemans, Everardus Otto

AU - Drilon, Alexander

PY - 2021/12

Y1 - 2021/12

N2 - Objectives: Single-agent heat shock protein 90 (HSP90) inhibition has demonstrated activity in oncogene-driven non-small cell and small cell lung cancers. SNX-5422 is an oral HSP90 inhibitor with increased activity in vitro with the addition of carboplatin and paclitaxel. Therefore, we conducted a phase 1, open-label, multicenter study to evaluate SNX-5422, carboplatin and paclitaxel followed by SNX-5422 maintenance in patients with advanced lung cancers. Materials and methods: In part 1 (3 + 3 dose escalation), SNX-5422 (50/75/100-mg/m2) was dosed every other day (qod) for 21 days (28-day cycle) for ≤4 cycles; carboplatin (AUC 5)-paclitaxel (175 mg/m2) was administered once every 3 weeks for ≤6 courses. In part 2 (maintenance), subjects who achieved at least stable disease in part 1 received 100 mg/m2 SNX-5422 monotherapy qod for 21 days (28-day cycle). Results: Twenty-three patients with advanced non-small cell lung cancer (NSCLC, n = 20) and small cell lung cancer (SCLC, n = 3) were enrolled. The median age was 60 years and 61% (n = 14/23) had ≥1 prior treatment regimens. The maximum tolerated dose of SNX-5422 was 100 mg/m2 qod in combination with carboplatin-paclitaxel. The most common treatment-related grade 3/4 adverse events (part 1/part 2) were diarrhea (26%/15%) and nausea (9%/0%). In response-evaluable patients with NSCLC, 33% (6/18) had a partial response, 56% (10/18) stable disease, and 11% (2/18) progressive disease. Patients who remained on single-agent SNX-5422 maintenance therapy ≥2 months (n = 9) had cancers enriched for oncogenic drivers (n = 3 KRAS mutation, n = 1 EGFR exon 20 mutation, n = 1 HER2 mutation, and n = 1 RET fusion). Conclusions: The triplet combination of SNX-5422, carboplatin and paclitaxel followed by maintenance SNX-5422 therapy was well-tolerated and showed anti-tumor activity. Cancers for which disease control on single-agent SNX-5422 maintenance was observed were enriched for oncogene-driven NSCLCs.

AB - Objectives: Single-agent heat shock protein 90 (HSP90) inhibition has demonstrated activity in oncogene-driven non-small cell and small cell lung cancers. SNX-5422 is an oral HSP90 inhibitor with increased activity in vitro with the addition of carboplatin and paclitaxel. Therefore, we conducted a phase 1, open-label, multicenter study to evaluate SNX-5422, carboplatin and paclitaxel followed by SNX-5422 maintenance in patients with advanced lung cancers. Materials and methods: In part 1 (3 + 3 dose escalation), SNX-5422 (50/75/100-mg/m2) was dosed every other day (qod) for 21 days (28-day cycle) for ≤4 cycles; carboplatin (AUC 5)-paclitaxel (175 mg/m2) was administered once every 3 weeks for ≤6 courses. In part 2 (maintenance), subjects who achieved at least stable disease in part 1 received 100 mg/m2 SNX-5422 monotherapy qod for 21 days (28-day cycle). Results: Twenty-three patients with advanced non-small cell lung cancer (NSCLC, n = 20) and small cell lung cancer (SCLC, n = 3) were enrolled. The median age was 60 years and 61% (n = 14/23) had ≥1 prior treatment regimens. The maximum tolerated dose of SNX-5422 was 100 mg/m2 qod in combination with carboplatin-paclitaxel. The most common treatment-related grade 3/4 adverse events (part 1/part 2) were diarrhea (26%/15%) and nausea (9%/0%). In response-evaluable patients with NSCLC, 33% (6/18) had a partial response, 56% (10/18) stable disease, and 11% (2/18) progressive disease. Patients who remained on single-agent SNX-5422 maintenance therapy ≥2 months (n = 9) had cancers enriched for oncogenic drivers (n = 3 KRAS mutation, n = 1 EGFR exon 20 mutation, n = 1 HER2 mutation, and n = 1 RET fusion). Conclusions: The triplet combination of SNX-5422, carboplatin and paclitaxel followed by maintenance SNX-5422 therapy was well-tolerated and showed anti-tumor activity. Cancers for which disease control on single-agent SNX-5422 maintenance was observed were enriched for oncogene-driven NSCLCs.

KW - EGFR wild-type

KW - HSP90 inhibitor

KW - NSCLC

KW - Platinum therapy

KW - SNX-5422

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UR - https://www.scopus.com/inward/citedby.url?scp=85116902528&partnerID=8YFLogxK

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C2 - 34655925

AN - SCOPUS:85116902528

SN - 0169-5002

VL - 162

SP - 23

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JO - Lung Cancer

JF - Lung Cancer

ER -

Phase 1 multicenter study of the HSP90 inhibitor SNX-5422 plus carboplatin and paclitaxel in patients with lung cancers

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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