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Dr. Jack West is a medical oncologist and thoracic oncology specialist, and Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center in Duarte, CA.

Heat Shock Protein Inhibition Provides Another Encouraging Signal for Some Lung Adenocarcinoma Patients with a Worse Prognosis
Mon, 07/09/2012 - 11:47
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

Historically, lung cancer patients with a KRAS mutation, which is the molecular marker that is actually most common in patients with NSCLC (about 20-25%), have not had extremely appealing treatment options.  In fact, the available data has largely led to the conclusion that both chemotherapy and EGFR inhibitor therapy tends to be, if anything, somewhat less effective for people with a KRAS mutation.  Despite some reason for hope in early research with a few novel therapies, there really hasn't been a good alternative that is specifically effective for KRAS mutation-positive patients until the data emerged from ASCO 2012 that showed very encouraging efficacy for KRAS mutation-positive, chemotherapy pre-treated patients with advanced NSCLC who received a combination of the MEK inhibitor selumetinib combined with the standard chemotherapy Taxotere (docetaxel), compared with Taxotere alone.  That work demonstrated some toxicity challenges with the novel agent, but regardless, it's always good to learn of another potentially fruitful avenue for improving patient outcomes.  Some phase II work with the heat shock protein (HSP90) inhibitor ganetespib (also known as STA-9090), also in combination with Taxotere, now shows a provocative signal of especially favorable activity in NSCLC patients with advanced NSCLC, at least those with an adenocarcinoma (disclosure: I participated in the phase II work with ganetespib).  To review heat shock protein inhibitors in a sentence, they act as a "chaperone protein" for many "client proteins" in several different cancer-related pathways and protects them from being broken down by the cell, which is what happens when a heat shock protein inhibitor like ganetespib is given. 

In preclinical studies, heat shock protein inhibitors are most effective when given in combination with conventional chemotherapy, though they also have some single agent activity.  Ganetespib also appears to be active in KRAS mutation-positive cancer cells, which led to particular interest in testing it in patients with this profile.  In fact, work with ganetespib as a single agent revealed that 8 of 13 patients (62%) with a KRAS mutation showed tumor shrinkage, as did 6 of the 8 (75%) patients with an ALK rearrangement.  The patients with KRAS mutations are represented by yellow bars, and the patients with an ALK rearrangement are represented by green bars, in the waterfall plot below (in which bars going down represent tumor shrinkage, and bars going up represent tumor progression, with the length of the bar corresponding with the extent of shrinkage or growth):


The results I'm describing now are from an interim analysis of a phase II study called GALAXY that was designed to test the benefit of adding ganetespib, given IV on days 1 and 15 of a 21 day treatment schedule, along with Taxotere on day 1 of the same 21 day schedule.  The primary endpoint is progression-free survival (PFS) in two subgroups: patients with a KRAS mutation, and the approximately 30% of patients with an elevated lactate dehydrogenase (LDH) level, which is associated with low oxygen levels in the cancer and overall worse outcomes for patients.  HSP90 inhibitors can block some of the effects of hypoxia (low oxygen levels) and may potentially be especially active in such patients.

The analysis thus far is based on 183 patients with both adenocarcinoma (N = 114)  and non-adenocarcinoma (N= 69) advanced NSCLC who had received prior first line chemotherapy, though subsequent review of the early data showed no evidence of benefit for the patients with non-adeno NSCLC (whose results were not presented, which is not really how it should be done), so the results highlighted are restricted to the findings in the patients with lung adenocarcinoma.

Overall, they found that the combination was well tolerated, with the main added side effect being a higher rate of diarrhea with ganetespib added (10 vs. 40%), and this was usually mild to moderate (only 2% of patients receiving the combination had grade 3 or higher diarrhea, vs. 0% of patients receiving Taxotere alone).  Other side effects were really comparable with what patients experienced with Taxotere alone.

The median PFS was longer in lung adenocarcinoma patients receiving the combination compared with Taxotere alone (4.2 vs. 2.9 months), but the more promising findings were in the two subsets.  In those with a KRAS mutation (N = 20), the median PFS was 4.2 vs. 1.6 for the combination vs. Taxotere alone, respectively.  For the lung adenocarcinoma patients with an elevated LDH (N=31), the median PFS was 4.2 vs. 1.4 months for the combination vs. Taxotere monotherapy, respectively.   And while still early and without stats offered, the overall survival curves appear very favorable for the combination arm:

So what can we make of these findings?  I absolutely find these results very encouraging, though it's important to remember that the numbers are small (the subsets that have looked most favorable have just 20 (for KRAS mutation) or 31 (for elevated LDH) patients in them.  But the point of the review of the data at this point was to assess whether the findings are promising enough to lead to expansion of this work into a phase III trial, and I certainly feel that these results achieve that threshold.  This trial will be seeking patients with a lung adenocarcinoma and will be particularly focused on demonstrating a benefit in patients with an elevated LDH and/or KRAS mutation.  These are patients who could use some new treatment options, and I will be eager to contribute to this trial being completed.

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