2016: Addition of onalespib to crizotinib prior to progression in pts with ALK-pos NSCLC: P2 Results

Summary

  • Hsp90 is required for proper ALK function
  • Onalespib (AT13387) is a second generation Hsp90 inhibitor
  • Onalespib in ALK-driven pre-clinical models:
    • Displays potent antitumor activity
    • Delays the onset of resistance
  • In the clinic, onalespib
    •  Has a safety profile consistent with the class
    • (diarrhea, mild transient visual changes)
    • PK & PD results support weekly dosing
    • – Has antitumor activity (PR) at a dose of 220 mg/m2 (D1,8,15 of 28 Day cycle)
  • Crizotinib (CZT) has demonstrated clinical activity in ALK-pos NSCLC
  • AT13387-05 is a 3-part, Phase 1-2 study in ALK-pos NSCLC
    • Part A (Phase 1 of the study demonstrated the safety of Onalespib/CZT in combination with some activity in progressing patients
    • Results are presented for Part B of the study, randomization to combination of Onalespib added to CZT vs CZT alone prior to development of resistance (Fig 2)

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Addition of onalespib to crizotinib prior to progression in pts with ALK-pos NSCLC: P2 Results

2015 AACR: Onalespib delays the emergence of resistance to erlotinig in EGFR-driven xenograft model

Summary

Kinase inhibitors have been used successfully in the clinic, but relapse is common due to the emergence of resistance. Inhibition of HSP90 leads to the depletion of oncogenic ‘client’ proteins and
the simultaneous inhibition of many signalling pathways. As such, the use of HSP90 inhibitors to overcome resistance has been widely investigated.

Onalespib (AT13387) is a potent, second generation HSP90 inhibitor, which has been studied in many preclinical models of kinase inhibitor resistance. Recent findings indicate that an upfront
combination of onalespib and either vemurafenib or crizotinib, in models of mutant BRAF melanoma or ALK-translocated non-small cell lung cancer (NSCLC), can delay the emergence of resistance
to these therapies (Smyth et al 2014, Wallis et al 2014). Here we have extended this work to a combination of onalespib and erlotinib in an EGFR-driven NSCLC model.

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2015 AACR: Onalespib delays the emergence of resistance to erlotinig in EGFR-driven xenograft model

2015 TAT: Combination of onalespib (AT13387) with crizotinib to treat or delay resistance in NSCLC

2015 TAT: Combination of onalespib (AT13387) with crizotinib to treat or delay resistance in NSCLC

2014: ESMO Study of HSP90 Inhibitor AT13387 alone and combo w/ Crizotinib in the treatment of NSCLC

Summary

  • Hsp90 is required for proper ALK function
  • AT13387 is a second generation Hsp90 inhibitor
  • AT13387 in ALK-driven pre-clinical models:
    • Displays potent antitumor activity
    • Delays the onset of resistance
  • In the clinic, AT133872
    • Has a safety profile consistent with the class
    • (diarrhea, mild transient visual changes)
      • PK & PD results support weekly dosing
      • Has antitumor activity (PR) at a dose of 220 mg/m2
        (D1,8,15 of 28 Day cycle)
  • Crizotinib (CZT) has demonstrated clinical activity in ALK-pos NSCLC3
  • AT13387-05 is a 3-part, Phase 1-2, randomized study

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2014: ESMO Study of HSP90 Inhibitor AT13387 alone and combo w/ Crizotinib in the treatment of NSCLC

2014: ESMO Phase 1/2 of AT13387, HSP90 Inhibitor, in combo with abiraterone acetate and prednisone

Summary

Heat Shock Protein 90 (HSP90) is an ATP-dependent molecular chaperone that assists in correct folding Of a Wide variety Of ‘client’ proteins (Androgen Receptor (AR), AKT, HER2 and CDK4).

ATI 3387 (AT) is a fragment derived, second-generation novel potent non-ansamycin HSP90 inhibitor (Kd:O.71 nM)1 with good tissue distribution, excellent in vivo anti-tumor activity and long tumor half life in preclinical models (65-78 hours).

ATI 3387 demonstrated anti-tumor activity in preclinical castration-resistant prostate cancer (CRPC) models2 and ho ds promise as a therapeutic agent by simultaneously down-regulating multiple aberrant signalling pathways.

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2014: ESMO Phase 1/2 of AT13387, HSP90 Inhibitor, in combo with abiraterone acetate and prednisone

2014 AACR: AT13387 combined with erlotinib improves response in EGFR-driven xenograft models of NSCL

Summary

Epidermal Growth Factor Receptor (EGFR) can be activated by point mutations e.g L858R or by deletions in exon19. A subset of non-small cell lung cancer (NSCLC) have activated EGFR and can be successfully treated with EGFR inhibitors such as erlotinib. However, resistance frequently develops to these inhibitors, often due to acquisition of a further T790M mutation in EGFR leading to relapse. Methods to improve response and delay resistance are therefore of value.

Inhibition of the chaperone, HSP90, leads to the depletion of many client proteins, including EGFR, and has the capacity to simultaneously affect many signalling pathways, offering an alternative strategy for targeting EGFR-driven disease.

AT13387 is a potent, second generation HSP90 inhibitor currently being tested in Phase 2 clinical trials. Here we investigated the effects of combining AT13387 and erlotinib in models of EGFR- driven NSCLC.

2014 AACR: AT13387 combined with erlotinib improves response in EGFR-driven xenograft models of NSCL

2014 TAT: HSP90 inhibition by AT13387 can overcome & delay appearance of resistance to TKI in lung

2014 TAT: HSP90 inhibition by AT13387 can overcome & delay appearance of resistance to TKI in lung

2013 WorldMelanoma: Combining AT13387 with vemurafenib delay emergence of resistance in preclin mode

2013 WorldMelanoma: Combining AT13387 with vemurafenib delay emergence of resistance in preclin mode

2013: IASLC WCLC AT13387 Displays Single Agent Activity in Erlotinib-Sensitive & -Resistant NSCLC

2013: IASLC WCLC AT13387 Displays Single Agent Activity in Erlotinib-Sensitive & -Resistant NSCLC