Adding HSP90 Inhibitor to Erlotinib in Lung Cancer Does Not Improve Response

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Adding the heat shock protein 90 (HP90) inhibitor, AUY922, to erlotinib therapy in metastatic lung cancer patients who progressed on erlotinib (Tarceva) alone did not provide a therapeutic benefit.

In a phase I/II clinical trial, the partial response rate was 16% (4 of 25 patients), but the combination resulted in high levels of toxicity including night blindness. The results of the trial are published in the Journal of Clinical Oncology.¹

An additional 10 patients had stable disease, and in four of these patients, their stable disease lasted 6 months. Of the four patients that responded, the median time on therapy was 14 weeks, and ranged from 8 to 77 weeks.

In a previous phase II clinical trial of previously treated lung cancer patients, including those with EGFR inhibitor resistant disease, the response rate to AUY922 monotherapy was 18% (12 of 66 patients responded).

Patients with EGFR-mutated lung cancer typically respond to oral, EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib (Iressa), or afatinib (Gilotrif), but patients inevitably progress as their cancer becomes resistant-within a median of 9 to 14 months after the start of therapy.

“The vast majority-if not all-patients with EGFR mutations who are treated with EGFR inhibitors eventually develop resistance,” said study author Melissa L. Johnson, MD, now the associate director of the Lung Cancer Research program at the Sarah Cannon Research Institute in Nashville, Tenn., but who was at Northwestern University in Chicago while this trial was conducted.

“About half of those patients with so-called "acquired resistance" are found to have a secondary mutation in EGFR, called EGFR T790M, which causes this clinical resistance to develop. While there are a number of third-generation EGFR inhibitors in development, which effectively inhibit EGFR T790M, at the time that this trial was designed, there were very few options available for patients with acquired resistance to EGFR-TKIs, except standard chemotherapy," said Johnson.

Because ceasing an initial TKI regimen can result in rapid disease progression or even death, EGFR TKIs are given in combination with a second line therapy. The rationale is that parts of the patients’ tumors are resistant to EGFR inhibition, but some parts remain sensitive to the therapy. The current trial tested this strategy, giving patients with signs of progression on erlotinib, an additional therapy-the HSP90 inhibitor AUY922.

AUY922 (Vernalis, Novartis) is an HSP90 inhibitor that causes degradation of HSP chaperones and their protein binding partners, including EGFR. In mouse xenograft models, AUY922 induces apoptosis in both tyrosine kinase inhibitor (TKI) sensitive and resistant EGFR-mutant cell lines, and reduced cell growth in those cell lines with the T790M mutation.

Two other HSP90 inhibitors, retaspimycin and ganetespib, have also been evaluated in patients with metastatic lung cancer. EGFR-mutated lung cancer patients treated with monotherapy retaspimycin had a response rate of 4%, and single-agent ganetespib produced no responses in this subset of patients.

Erlotinib was given once a day as an oral dose on a 28 day cycle, and AUY922 was given intravenously once per week. In the phase I portion of the trial, the maximum tolerated dose was determined to be 70 mg/m² IV of AUY922 once per week, and 150 mg orally once per day of erlotinib. Eighteen patients were part of the dose-escalation phase I portion and 25 were part of the phase II portion, treated at the maximum tolerated dose. Patients had a median of two prior therapies. Forty-three percent of patients (16 of 37) had an EGFR T790M mutation at trial enrollment.

The most common drug-related adverse events among the dose-escalating cohort were diarrhea, rash, nausea, and fatigue. Three phase I patients discontinued therapy for grade 2 night blindness, which was reversible once when AUY922 therapy was stopped.

The most frequent drug related adverse events among patients in the phase II portion of the trial were diarrhea, night blindness, and skin rash. Night blindness was generally of grade 1 severity, but occurred in 72% of patients. Asymptomatic elevations in glucose (92%), AST/ALT (84%), and bilirubin (64%), as well as hypoalbuminemia (84%) and hyponatremia (68%), were also observed. Five patients experienced asymptomatic grade 3 lymphopenia.

Four patients (21%) in the phase II portion discontinued due to toxicity: two patients with grade 3 AST/ALT abnormalities, one with grade 2 night blindness, and one with grade 3 diarrhea/colitis. No patients experienced grade 4 or 5 toxicities.

The addition of erlotinib did not improve response rates for patients with EGFR-driven tumors. “We showed the combination of HSP90 inhibitor AUY922 and erlotinib resulted in an approxately equivalent response rate to patients with similar molecular characteristics on other trials treated with AUY922 alone, and with perhaps greater toxicities than the single-agent HSP90 inhibitor,” said Johnson.  “Although the pharmacokinetic studies we performed did not indicate drug-drug interactions, we wondered if the addition of erlotinib seemed to enhance the side effect profile of AUY922,” she added.

“The results were disappointing, and coincidently suggested that patients with ALK rearrangements-ALK is also a client protein of HSP90-might also be effectively treated with this class of drugs. However, we know that a small percentage of patients with EGFR mutations treated with EGFR-TKIs will experience a disease-related “flare” of symptoms and radiographic progression if EGFR-TKIs are stopped abruptly… and suggested that the HSP90 inhibitor AUY922 be combined with erlotinib for this trial to eliminate the chance of disease flare and enhance the possibility of efficacy for patients with EGFR mutations.”

No additional studies testing this combination are planned.

References:

• Johnson ML, Yu HA, Hart EM, et al. (2015). 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. Journal of Clinical Oncology.