Erlotinib and Onalespib Lactate Focused on EGFR Exon 20 Insertion Non-Small Cell Lung Cancer (NSCLC): A California Cancer Consortium Phase I/II Trial (NCI 9878)

Jonathan W Riess, Karen L Reckamp, Paul Frankel, Jeffrey Longmate, Karen A Kelly, David R Gandara, Caroline M Weipert, Victoria M Raymond, Harold N Keer, Philip C Mack, Edward M Newman, Primo N Lara Jr, Jonathan W Riess, Karen L Reckamp, Paul Frankel, Jeffrey Longmate, Karen A Kelly, David R Gandara, Caroline M Weipert, Victoria M Raymond, Harold N Keer, Philip C Mack, Edward M Newman, Primo N Lara Jr

Abstract

Background: Onalespib is a novel heat shock protein 90 inhibitor (HSP90i). Previous preclinical and clinical studies with HSP90i have demonstrated activity in EGFR-mutant non-small cell lung cancer (NSCLC). This study sought to determine the safety and tolerability of onalespib plus erlotinib in EGFR-mutant NSCLC and to evaluate the preliminary efficacy of the combination in epidermal growth factor receptor exon 20 insertion (EGFRex20ins) NSCLC.

Patients and methods: Standard 3+3 dose escalation was followed by a phase II expansion in EGFRex20ins. The phase II component targeted a response rate of 25% versus a background rate of 5%. Prospective next-generation sequencing (NGS) of 70 cancer-related genes, including EGFR, via plasma circulating tumor DNA (ctDNA) was performed. Toxicity was graded by Common Terminology Criteria for Adverse Events (CTCAE), version 4, and response was determined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1.

Results: Eleven patients were treated (nine dose escalation, two dose expansion). Two dose-limiting toxicities (DLTs) occurred in dose level (DL) 0 and zero in DL -1 (minus). In 10 EGFRex20ins patients, no responses were observed, median progression-free survival was 5.4 months (95% confidence interval, 0.9-5.7), and the disease control rate (DCR) was 40% (median, 3.5 months). EGFRex20ins was detected in nine of 10 ctDNA samples at baseline; on-treatment ctDNA clearance was not observed. Grade 3 diarrhea was the predominant toxicity in 45% of patients. The recommended phase II dose is DL -1 (minus): erlotinib 150 mg orally every morning and onalespib 120 mg/m2 intravenously on days 1, 8, and 15 every 28 days.

Conclusion: Overlapping toxicities of erlotinib and onalespib, mainly diarrhea, limited the tolerability of this combination, and limited clinical activity was observed, so the trial was closed early. Plasma EGFRex20ins ctDNA was detected in the majority of patients; failure to clear ctDNA was consistent with lack of tumor response (NCT02535338).

Keywords: EGFR Exon 20 insertion; EGFR tyrosine kinase inhibitor; Heat shock protein 90; Heat shock protein inhibitors; circulating tumor DNA.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1
Figure 1
Diagram of Dose Escalation and Expansion Cohort. Abbreviations: EGFR = epidermal growth factor receptor; TKI = tyrosine kinase inhibitor.
Figure 2
Figure 2
A, Waterfall Plot of Best Response and B, Months on Treatment Among EGFRex20ins NSCLC. Abbreviation: EGFRex20ins = EGFR exon 20 insertion.
Figure 3
Figure 3
PFS in EGFRex20ins Patients Treated with Erlotinib and Onalespib. Abbreviations: EGFRex20ins = EGFR exon 20 insertion; PFS = progression-free survival.
Figure 4
Figure 4
A, Dynamics of EGFRex20ins VAF From Plasma ctDNA. Nine of 10 Patients With EGFRex20ins Were Detected at Baseline. No Patients With Detectable EGFRex20ins ctDNA at Baseline Cleared the Mutation During Treatment, Corresponding With the Lack of Clinical or Radiographic Response. B, Baseline VAF and Months on Treatment. Cutpoint of 5% EGFRex20ins VAF Was Prognostic for Time on Treatment. Abbreviations: ctDNA = circulating tumor DNA; EGFRex20ins = EGFR exon 20 insertion; VAF = variant allele fraction

References

    1. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735–742.
    1. Yasuda H, Kobayashi S, Costa DB. EGFR exon 20 insertion mutations in non-small-cell lung cancer: preclinical data and clinical implications. Lancet Oncol 2012;13:e23–e31.
    1. Riess JW, Gandara DR, Frampton GM, et al. Diverse EGFR exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC. J Thorac Oncol 2018;13:1560–1568.
    1. Yasuda H, Park E, Yun CH, et al. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med 2013;5:216ra177.
    1. Floc’h N, Martin MJ, Riess JW, et al. Antitumor activity of osimertinib, an irreversible mutant-selective EGFR tyrosine kinase inhibitor, in NSCLC harboring EGFR exon 20 insertions. Mol Cancer Ther 2018;17:885–896.
    1. Piotrowska Z, Fintelmann FJ, Sequist LV, Jahagirdar B. Response to osimertinib in an EGFR exon 20 insertion-positive lung adenocarcinoma. J Thorac Oncol 2018;13:e204–e206.
    1. Robichaux JP, Elamin YY, Tan Z, et al. Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer. Nat Med 2018;24:638–646.
    1. Janne PA, Neal JW, Camidge DR, et al. Antitumor activity of TAK-788 in NSCLC with EGFR exon 20 insertions. J Clin Oncol 2019;37:9007.
    1. Piotrowska Z, Wang Y, Sequist LV, Ramalingam SS. ECOG-ACRIN 5162: a phase II study of osimertinib 160 mg in NSCLC with EGFR exon 20 insertions. J Clin Oncol 2020;38:9513.
    1. Park K, John T, Kim S, et al. Amivantamab (JNJ-61186372), an anti-EGFR-MET bispecific antibody, in patients with EGFR exon 20 insertion (exon20ins)-mutated non-small cell lung cancer (NSCLC). J Clin Oncol 2020;38:9513.
    1. Neckers L, Workman P. Hsp90 molecular chaperone inhibitors: are we there yet? Clin Cancer Res 2012;18:64–76.
    1. Xu W, Soga S, Beebe K, et al. Sensitivity of epidermal growth factor receptor and ErbB2 exon 20 insertion mutants to Hsp90 inhibition. Br J Cancer 2007;97:741–744.
    1. Jorge SE, Lucena-Araujo AR, Yasuda H, et al. EGFR exon 20 insertion mutations display sensitivity to Hsp90 inhibition in preclinical models and lung adenocarcinomas. Clin Cancer Res 2018;24:6548–6555.
    1. Piotrowska Z, Costa DB, Oxnard GR, et al. Activity of the Hsp90 inhibitor luminespib among non-small-cell lung cancers harboring EGFR exon 20 insertions. Ann Oncol 2018;29:2092–2097.
    1. Shimamura T, Lowell AM, Engelman JA, Shapiro GI. Epidermal growth factor receptors harboring kinase domain mutations associate with the heat shock protein 90 chaperone and are destabilized following exposure to geldanamycins. Cancer Res 2005;65:6401–6408.
    1. Garcia-Carbonero R, Carnero A, Paz-Ares L. Inhibition of HSP90 molecular chaperones: moving into the clinic. Lancet Oncol 2013;14:e358–e369.
    1. Graham B, Curry J, Smyth T, et al. The heat shock protein 90 inhibitor, AT13387, displays a long duration of action in vitro and in vivo in non-small cell lung cancer. Cancer Sci 2012;103:522–527.
    1. Smyth T, Van Looy T, Curry JE, et al. The HSP90 inhibitor, AT13387, is effective against imatinib-sensitive and -resistant gastrointestinal stromal tumor models. Mol Cancer Ther 2012;11:1799–1808.
    1. Smyth T, Paraiso KHT, Hearn K, et al. Inhibition of HSP90 by AT13387 delays the emergence of resistance to BRAF inhibitors and overcomes resistance to dual BRAF and MEK inhibition in melanoma models. Mol Cancer Ther 2014;13:2793–2804.
    1. Courtin A, Smyth T, Hearn K, et al. Emergence of resistance to tyrosine kinase inhibitors in non-small-cell lung cancer can be delayed by an upfront combination with the HSP90 inhibitor onalespib. Br J Cancer 2016;115:1069–1077.
    1. Odegaard JI, Vincent JJ, Mortimer S, et al. Validation of a plasma-based comprehensive cancer genotyping assay utilizing orthogonal tissue- and plasma-based methodologies. Clin Cancer Res 2018;24:3539–3549.
    1. Zill OA, Banks KC, Fairclough SR, et al. The landscape of actionable genomic alterations in cell-free circulating tumor DNA from 21,807 advanced cancer patients. Clin Cancer Res 2018;24:3528–3538.
    1. Schwaederle MC, Patel SP, Husain H, et al. Utility of genomic assessment of blood-derived circulating tumor DNA (ctDNA) in patients with advanced lung adenocarcinoma. Clin Cancer Res 2017;23:5101–5111.
    1. Johnson ML, Yu HA, Hart EM, et al. Phase I/II study of HSP90 inhibitor AUY922 and erlotinib for EGFR-mutant lung cancer with acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors. J Clin Oncol 2015;33:1666–1673.
    1. Shapiro GI, Kwak E, Dezube BJ, et al. First-in-human phase I dose escalation study of a second-generation non-ansamycin HSP90 inhibitor, AT13387, in patients with advanced solid tumors. Clin Cancer Res 2015;21:87–97.
    1. Rolfo C, Mack PC, Scagliotti GV, et al. Liquid biopsy for advanced non-small cell lung cancer (NSCLC): a statement paper from the IASLC. J Thorac Oncol 2018;13:1248–1268.
    1. Mok T, Wu YL, Lee JS, et al. Detection and dynamic changes of EGFR mutations from circulating tumor DNA as a predictor of survival outcomes in NSCLC patients treated with first-line intercalated erlotinib and chemotherapy. Clin Cancer Res 2015;21:3196–3203.
    1. Aggarwal C, Davis CW, Mick R, et al. Influence of TP53 mutation on survival in patients with advanced EGFR-mutant non-small-cell lung cancer. JCO Precis Oncol 2018;2018 PO.18.00107.
    1. Pairawan S, Hess KR, Janku F, et al. Cell-free circulating tumor DNA variant allele frequency associates with survival in metastatic cancer. Clin Cancer Res 2020;26:1924–1931.
    1. Schwaederle M, Husain H, Fanta PT, et al. Use of liquid biopsies in clinical oncology: pilot experience in 168 patients. Clin Cancer Res 2016;22:5497–5505.
    1. Piotrowska Z, Wang Y, Sequist LV, Ramalingam S. ECOG-ACRIN 5162: a phase II study of osimertinib 160 mg in NSCLC with EGFR exon 20 insertions. J Clin Oncol 2020;38:9513.
    1. Codony-Servat J, Codony-Servat C, Viteri S, et al. Hsp90 inhibitors enhance the antitumoral effect of osimertinib and overcome osimertinib resistance in non-small cell lung cancer cell models. Ann Oncol 2019;30:v10–v11.
    1. Cerami E, et al. The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery 2012;2(5):401–404. doi:10.1158/-12-0095.
    1. Gao J, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal 2013;2(6):269. doi:10.1126/scisignal.2004088.

Source: PubMed

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