Further Development of Hsp90 Inhibitor in NSCLC Remains Uncertain

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In December 2014, Novartis announced it would cease further development of the luminespib program.
In December 2014, Novartis announced it would cease further development of the luminespib program.

More than one-third of patients with non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions (ins20) treated with the Hsp90 inhibitor luminespib achieved stable disease or better for longer than 3 months, according to a recent study.1

These results suggest that luminespib may be active for this patient subgroup, which generally has disease that is refractory to first- or second-generation EGFR inhibitors.

In the phase 2 study, 29 patients with stage IV NSCLC with EGFR ins20 were assigned to receive a standard starting dose of luminespib 70 mg/m2 weekly. All patients had been treated with at least 1 therapy prior to enrollment in the study.

In the overall intent-to-treat population, the overall response rate was 17%; all responses were partial responses. Stable disease lasting longer than 3 months was achieved in 6 patients. This translated into an effectiveness of 38%.

Two patients were later found to be EGFR ins20-negative, and these 2 patients both had stable disease lasting less than 3 months. When these 2 patients were excluded from the analysis, the overall response rate was 19% with a target rate of effectiveness of 41%.

The median progression-free survival was 2.8 months and the median overall survival was 9.9 months. When the 2 EGFR ins20-negative patients were excluded, this increased to 3.3 months and 12.8 months, respectively.

The most common treatment-related adverse events were diarrhea (83%), visual changes (76%), and fatigue (45%).

In December 2014, Novartis announced it would cease further development of the luminespib program, and as a result, the drug's codeveloper, Vernalis plc, gained back the rights to the drug. Ligand Pharmaceuticals announced on October 10, 2018, the acquisition of Vernalis, which will now operate as a subsidiary of Ligand.2

“The development of luminespib was halted during the conduct of our study and the trial had to be stopped prematurely when all available drug supply expired in February 2017,” the researchers noted. “This highlights a major limitation of our current system of drug development, and the need for innovative strategies to provide ongoing treatment to responding patients when drug supplies are limited.”

The authors noted that other targeted therapies for lung cancers harboring EGFR ins20 mutations — specifically, tyrosine kinase inhibitors (TKIs) — are under development at other pharmaceutical companies, including Spectrum Pharmaceuticals, Inc's poziotinib, currently in phase 2 studies (ClinicalTrials.gov Identifier: NCT03066206); TAK-788 from Ariad Pharmaceuticals/Takeda (ClinicalTrials.gov Identifier: NCT02716116), now in an ongoing phase 1 study; and the currently recruiting phase 2 study on osimertinib that is being run by the National Cancer Institute (ClinicalTrials.gov Identifier: NCT03191149).

“We are optimistic that one or more of these new drugs will lead to both activity and a tolerable toxicity profile, with eventual regulatory approval in this underserved patient population,” the authors of the study wrote about the TKIs in the pipeline. “Nevertheless, we see a role for further study of luminespib or other hsp90 inhibitors, which act by a different mechanism than TKIs and could potentially benefit patients who do not respond to or become resistant to other novel therapies.”

Disclosure: The original study was funded by Novartis Pharmaceuticals Corporation. For a full list of disclosures, please refer to the original study.

References

  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 [published online October 23, 2018]. Ann Oncol. doi: 10.1093/annonc/mdy336
  2. Ligand Pharmaceuticals Incorporated. Ligand announces the close of its acquisition of Vernalis [press release]. https://www.ligand.com/news-events/press-releases/detail/362/. Published October 10, 2018. Accessed October 31, 2018.

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