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William E. Lawler



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    P2.13 - Targeted Therapy (Not CME Accredited Session) (ID 962)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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      P2.13-39 - A Phase Ib Trial of the HSP90 Inhibitor AUY922 in Combination with Pemetrexed in Metastatic Non-Squamous, Non-Small Cell Lung Cancer Patients (ID 13953)

      16:45 - 18:00  |  Author(s): William E. Lawler

      • Abstract
      • Slides

      Background

      AUY922 demonstrates preclinical activity in non-small cell lung cancer (NSCLC) cell lines by potently inhibiting HSP90. As a single-agent, AUY922 showed clinical activity for NSCLC patients in a phase II trial, particularly in those with driver mutations in epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), client proteins of HSP90. We previously demonstrated that AUY922 reliably decreases dihydrofolate reductase (DHFR) mRNA expression. Therefore, we conducted a phase Ib trial of the combination of AUY922 with pemetrexed, an antifolate inhibitor of DHFR.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      In the dose-escalation portion, 9 patients with previously-treated metastatic non-squamous NSCLC were treated using a standard 3 + 3 design with pemetrexed at the standard 500 mg/m2 dose, plus: AUY922 40 mg/m2, 55 mg/m2, or 70 mg/m2 per week, respectively. After the maximum tolerated dose (MTD) was determined, an additional 4 patients were treated at the MTD. The primary endpoint was safety and tolerability.

      4c3880bb027f159e801041b1021e88e8 Result

      Of 13 total patients, 9 (70%) harbored an EGFR mutation. Two grade 3 dose-limiting toxicities were observed in the 70 mg/m2 cohort (thrombocytopenia and supraventricular tachycardia). Therefore, the MTD was determined to be 55 mg/m2 with pemetrexed. At the MTD, 71% (n=5) required a dose reduction, with a median relative dose intensity (RDI) of 88%. Common drug-related adverse events (DRAE) included ocular toxicity or visual disturbances (n=9, 70%), fatigue (n=6, 46%), diarrhea (n=5, 38%), anemia (n=5, 38%), anorexia (n=4, 31%), and nausea (n=3, 23%). There were no grade 4-5 events. Maximum serum concentration (Cmax) of AUY922 was associated with increased grade 2 DRAEs (rs = 0.74, p < 0.01). The volume of distribution (VZ) was inversely associated with number of DRAEs (rs = -0.81, p = 0.004) and number of ophthalmologic related DRAEs (rs = -0.65, p = 0.04). The best response was partial response in one patient for 20 months, prior to expiration of all AUY922. Immunohistochemistry of available pre-treatment tumor tissue (n = 10) revealed that this responder was also the only patient with tumor DHFR cytoplasmic and membranous pattern staining (2 to 3+ intensity).

      8eea62084ca7e541d918e823422bd82e Conclusion

      In patients with previously treated metastatic non-squamous NSCLC, the MTD of AUY922 in combination with pemetrexed was determined to be 55 mg/m2 per week. DHFR expression was seen only in the one long-term responder, but relevance is difficult to determine based on limited patient number based in part to closure of the study for lack of unexpired drug. Tolerability of AUY922 with pemetrexed is limited by ocular toxicity.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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